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Hallam TM, Sharp SJ, Andreadi A, Kavanagh D. Complement factor I: Regulatory nexus, driver of immunopathology, and therapeutic. Immunobiology 2023; 228:152410. [PMID: 37478687 DOI: 10.1016/j.imbio.2023.152410] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/23/2023] [Accepted: 06/01/2023] [Indexed: 07/23/2023]
Abstract
Complement factor I (FI) is the nexus for classical, lectin and alternative pathway complement regulation. FI is an 88 kDa plasma protein that circulates in an inactive configuration until it forms a trimolecular complex with its cofactor and substrate whereupon a structural reorganization allows the catalytic triad to cleave its substrates, C3b and C4b. In keeping with its role as the master complement regulatory enzyme, deficiency has been linked to immunopathology. In the setting of complete FI deficiency, a consumptive C3 deficiency results in recurrent infections with encapsulated microorganisms. Aseptic cerebral inflammation and vasculitic presentations are also less commonly observed. Heterozygous mutations in the factor I gene (CFI) have been demonstrated to be enriched in atypical haemolytic uraemic syndrome, albeit with a very low penetrance. Haploinsufficiency of CFI has also been associated with decreased retinal thickness and is a strong risk factor for the development of age-related macular degeneration. Supplementation of FI using plasma purified or recombinant protein has long been postulated, however, technical difficulties prevented progression into clinical trials. It is only using gene therapy that CFI supplementation has reached the clinic with GT005 in phase I/II clinical trials for geographic atrophy.
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Affiliation(s)
- T M Hallam
- Gyroscope Therapeutics Limited, A Novartis Company, Rolling Stock Yard, London N7 9AS, UK; Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne NE1 7RU, UK; National Renal Complement Therapeutics Centre, Building 26, Royal Victoria Infirmary, UK
| | - S J Sharp
- Gyroscope Therapeutics Limited, A Novartis Company, Rolling Stock Yard, London N7 9AS, UK
| | - A Andreadi
- Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne NE1 7RU, UK; National Renal Complement Therapeutics Centre, Building 26, Royal Victoria Infirmary, UK
| | - D Kavanagh
- Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne NE1 7RU, UK; National Renal Complement Therapeutics Centre, Building 26, Royal Victoria Infirmary, UK; NIHR Newcastle Biomedical Research Centre, Biomedical Research Building, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK.
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Kavanagh D, Greenbaum LA, Bagga A, Karki RG, Chen CW, Vasudevan S, Charney A, Dahlke M, Fakhouri F. Design and Rationale of the APPELHUS Phase 3 Open-Label Study of Factor B Inhibitor Iptacopan for Atypical Hemolytic Uremic Syndrome. Kidney Int Rep 2023; 8:1332-1341. [PMID: 37441479 PMCID: PMC10334406 DOI: 10.1016/j.ekir.2023.04.029] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/17/2023] [Accepted: 04/24/2023] [Indexed: 07/15/2023] Open
Abstract
Introduction Atypical hemolytic uremic syndrome (aHUS) is a rare, progressive, and life-threatening form of thrombotic microangiopathy (TMA) which is caused by dysregulation of the alternative complement pathway (AP). Complement inhibition is an effective therapeutic strategy in aHUS, though current therapies require intravenous administration and increase the risk of infection by encapsulated organisms, including meningococcal infection. Further studies are required to define the optimal duration of existing therapies, and to identify new agents that are convenient for long-term administration. Iptacopan (LNP023) is an oral, first-in-class, highly potent, proximal AP inhibitor that specifically binds factor B (FB). In phase 2 studies of IgA nephropathy, paroxysmal nocturnal hemoglobinuria, and C3 glomerulopathy, iptacopan inhibited the AP, showed clinically relevant benefits, and was well tolerated. Iptacopan thus has the potential to become an effective and safe treatment for aHUS, with the convenience of oral administration. Methods Alternative Pathway Phase III to Evaluate LNP023 in aHUS (APPELHUS; NCT04889430) is a multicenter, single-arm, open-label, phase 3 study to evaluate the efficacy and safety of iptacopan in patients (N = 50) with primary complement-mediated aHUS naïve to complement inhibitor therapy (including anti-C5). Eligible patients must have evidence of TMA (platelet count <150 × 109/l, lactate dehydrogenase ≥1.5 × upper limit of normal, hemoglobin ≤ lower limit of normal, serum creatinine ≥ upper limit of normal) and will receive iptacopan 200 mg twice daily. The primary objective is to assess the proportion of patients achieving complete TMA response without the use of plasma exchange or infusion or anti-C5 antibody during 26 weeks of iptacopan treatment. Conclusion APPELHUS will determine if iptacopan is safe and efficacious in patients with aHUS.
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Affiliation(s)
- David Kavanagh
- National Renal Complement Therapeutics Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK, and Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Larry A. Greenbaum
- Division of Pediatric Nephrology, Emory School of Medicine and Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Arvind Bagga
- Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Rajeshri G. Karki
- Clinical Development and Analytics Group, Cardiovascular, Renal and Metabolism Development Unit, Novartis Pharma, East Hanover, New Jersey, USA
| | - Chien-Wei Chen
- Clinical Development and Analytics Group, Cardiovascular, Renal and Metabolism Development Unit, Novartis Pharma, East Hanover, New Jersey, USA
| | - Sajita Vasudevan
- Chief Medical Office and Patient Safety, Novartis Healthcare, Hyderabad, India
| | - Alan Charney
- Clinical Development and Analytics Group, Cardiovascular, Renal and Metabolism Development Unit, Novartis Pharma, East Hanover, New Jersey, USA
| | - Marion Dahlke
- Clinical Development and Analytics Group, Cardiovascular, Renal and Metabolism Development Unit, Novartis Pharma, Basel, Switzerland
| | - Fadi Fakhouri
- Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
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Glover EK, Smith-Jackson K, Brocklebank V, Wilson V, Walsh PR, Montgomery EK, Wong EKS, Johnson S, Malina M, Kavanagh D, Sheerin NS. Assessing the Impact of Prophylactic Eculizumab on Renal Graft Survival in Atypical Hemolytic Uremic Syndrome. Transplantation 2023; 107:994-1003. [PMID: 36413152 PMCID: PMC10065821 DOI: 10.1097/tp.0000000000004355] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 07/22/2022] [Accepted: 08/10/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND Atypical hemolytic uremic syndrome (aHUS) is a rare cause of end-stage kidney disease and associated with poor outcomes after kidney transplantation from early disease recurrence. Prophylactic eculizumab treatment at the time of transplantation is used in selected patients with aHUS. We report a retrospective case note review describing transplant outcomes in patients with aHUS transplanted between 1978 and 2017, including those patients treated with eculizumab. METHODS The National Renal Complement Therapeutics Centre database identified 118 kidney transplants in 86 recipients who had a confirmed diagnosis of aHUS. Thirty-eight kidney transplants were performed in 38 recipients who received prophylactic eculizumab. The cohort not treated with eculizumab comprised 80 transplants in 60 recipients and was refined to produce a comparable cohort of 33 transplants in 32 medium and high-risk recipients implanted since 2002. Complement pathway genetic screening was performed. Graft survival was censored for graft function at last follow-up or patient death. Graft survival without eculizumab treatment is described by complement defect status and by Kidney Disease: Improving Global Outcomes risk stratification. RESULTS Prophylactic eculizumab treatment improved renal allograft survival ( P = 0.006) in medium and high-risk recipients with 1-y survival of 97% versus 64% in untreated patients. Our data supports the risk stratification advised by Kidney Disease: Improving Global Outcomes. CONCLUSIONS Prophylactic eculizumab treatment dramatically improves graft survival making transplantation a viable therapeutic option in aHUS.
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Affiliation(s)
- Emily K Glover
- National Renal Complement Therapeutics Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK
| | - Kate Smith-Jackson
- National Renal Complement Therapeutics Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK
- NIHR Newcastle Biomedical Research Centre, Biomedical Research Building, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
| | - Vicky Brocklebank
- National Renal Complement Therapeutics Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK
- NIHR Newcastle Biomedical Research Centre, Biomedical Research Building, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
| | - Valerie Wilson
- National Renal Complement Therapeutics Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - Patrick R Walsh
- National Renal Complement Therapeutics Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK
| | - Emma K Montgomery
- National Renal Complement Therapeutics Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - Edwin K S Wong
- National Renal Complement Therapeutics Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK
| | - Sally Johnson
- National Renal Complement Therapeutics Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK
- NIHR Newcastle Biomedical Research Centre, Biomedical Research Building, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
- Great North Children's Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Michal Malina
- National Renal Complement Therapeutics Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK
- Great North Children's Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - David Kavanagh
- National Renal Complement Therapeutics Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK
- NIHR Newcastle Biomedical Research Centre, Biomedical Research Building, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
| | - Neil S Sheerin
- National Renal Complement Therapeutics Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK
- NIHR Newcastle Biomedical Research Centre, Biomedical Research Building, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
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Wong EKS, Hallam TM, Brocklebank V, Walsh PR, Smith-Jackson K, Shuttleworth VG, Cox TE, Anderson HE, Barlow PN, Marchbank KJ, Harris CL, Kavanagh D. Functional Characterization of Rare Genetic Variants in the N-Terminus of Complement Factor H in aHUS, C3G, and AMD. Front Immunol 2021; 11:602284. [PMID: 33519811 PMCID: PMC7840601 DOI: 10.3389/fimmu.2020.602284] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 11/25/2020] [Indexed: 02/03/2023] Open
Abstract
Membranoproliferative glomerulonephritis (MPGN), C3 glomerulopathy (C3G), atypical haemolytic uraemic syndrome (aHUS) and age-related macular degeneration (AMD) have all been strongly linked with dysfunction of the alternative pathway (AP) of complement. A significant proportion of individuals with MPGN, C3G, aHUS and AMD carry rare genetic variants in the CFH gene that cause functional or quantitative deficiencies in the factor H (FH) protein, an important regulator of the AP. In silico analysis of the deleteriousness of rare genetic variants in CFH is not reliable and careful biochemical assessment remains the gold standard. Six N-terminal variants of uncertain significance in CFH were identified in patients with these diseases of the AP and selected for analysis. The variants were produced in Pichia Pastoris in the setting of FH CCPs 1-4, purified by nickel affinity chromatography and size exclusion and characterized by surface plasmon resonance and haemolytic assays as well as by cofactor assays in the fluid phase. A single variant, Q81P demonstrated a profound loss of binding to C3b with consequent loss of cofactor and decay accelerating activity. A further 2 variants, G69E and D130N, demonstrated only subtle defects which could conceivably over time lead to disease progression of more chronic AP diseases such as C3G and AMD. In the variants S159N, A161S, and M162V any functional defect was below the capacity of the experimental assays to reliably detect. This study further underlines the importance of careful biochemical assessment when assigning functional consequences to rare genetic variants that may alter clinical decisions for patients.
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Affiliation(s)
- Edwin K. S. Wong
- Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
| | - Thomas M. Hallam
- Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
| | - Vicky Brocklebank
- Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
| | - Patrick R. Walsh
- Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
| | - Kate Smith-Jackson
- Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
| | - Victoria G. Shuttleworth
- Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
| | - Thomas E. Cox
- Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
| | - Holly E. Anderson
- Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
| | - Paul Nigel Barlow
- School of Chemistry, Joseph Black Building, University of Edinburgh, David Brewster Road, Edinburgh, United Kingdom
| | - Kevin James Marchbank
- Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
| | - Claire L. Harris
- Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
| | - David Kavanagh
- Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
- NIHR Newcastle Biomedical Research Centre, Biomedical Research Building, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom
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Turkmen K, Baloglu I, Ozer H. C3 glomerulopathy and atypical hemolytic uremic syndrome: an updated review of the literature on alternative complement pathway disorders. Int Urol Nephrol 2021; 53:2067-2080. [PMID: 33389509 DOI: 10.1007/s11255-020-02729-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 12/02/2020] [Indexed: 11/30/2022]
Abstract
The complement system plays a significant role within the pathological process of C3 glomerulopathy (C3GP) and atypical hemolytic uremic syndrome (aHUS). In daily practice, clinicians should differentiate the subgroups of C3GP because of they should apply different treatment modalities. In the past, C3GP was considered as a part of membranoproliferative glomerulonephritis (MPGN). MPGN is defined as glomerular capillary thickening secondary to the synthesis of the new glomerular basement membrane and mesangial cellular hyperplasia with mesangial matrix expansion. Atypical hemolytic uremic syndrome is an ultra-rare disease that can be outlined by the triad of Coombs negative microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Recent advances demonstrated that these diseases share common abnormalities of the control of the alternative complement system. Therefore, nowadays, most researchers advocate that there may be overlap in the pathogenesis of C3GP and aHUS. This review will provide recent novel mechanisms and treatment options in these diseases. For the purposes that we mentioned above and to help clinicians, we aimed to describe the etiology, pathophysiology, and treatment of C3GP and aHUS in this comprehensive review.
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Affiliation(s)
- Kultigin Turkmen
- Department of Nephrology, Necmettin Erbakan University Meram School of Medicine, Konya, Turkey.
| | - Ismail Baloglu
- Department of Nephrology, Necmettin Erbakan University Meram School of Medicine, Konya, Turkey
| | - Hakan Ozer
- Department of Nephrology, Necmettin Erbakan University Meram School of Medicine, Konya, Turkey
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Infante B, Rossini M, Leo S, Troise D, Netti GS, Ranieri E, Gesualdo L, Castellano G, Stallone G. Recurrent Glomerulonephritis after Renal Transplantation: The Clinical Problem. Int J Mol Sci 2020; 21:ijms21175954. [PMID: 32824988 PMCID: PMC7504691 DOI: 10.3390/ijms21175954] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 07/30/2020] [Accepted: 08/17/2020] [Indexed: 12/22/2022] Open
Abstract
Glomerulonephritis (GN) continues to be one of the main causes of end-stage kidney disease (ESKD) with an incidence rating from 10.5% to 38.2%. Therefore, recurrent GN, previously considered to be a minor contributor to graft loss, is the third most common cause of graft failure 10 years after renal transplantation. However, the incidence, pathogenesis, and natural course of recurrences are still not completely understood. This review focuses on the most frequent diseases that recur after renal transplantation, analyzing rate of recurrence, epidemiology and risk factors, pathogenesis and bimolecular mechanisms, clinical presentation, diagnosis, and therapy, taking into consideration the limited data available in the literature. First of all, the risk for recurrence depends on the type of glomerulonephritis. For example, recipient patients with anti-glomerular basement membrane (GBM) disease present recurrence rarely, but often exhibit rapid graft loss. On the other hand, recipient patients with C3 glomerulonephritis present recurrence in more than 50% of cases, although the disease is generally slowly progressive. It should not be forgotten that every condition that can lead to chronic graft dysfunction should be considered in the differential diagnosis of recurrence. Therefore, a complete workup of renal biopsy, including light, immunofluorescence and electron microscopy study, is essential to provide the diagnosis, excluding alternative diagnosis that may require different treatment. We will examine in detail the biomolecular mechanisms of both native and transplanted kidney diseases, monitoring the risk of recurrence and optimizing the available treatment options.
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Affiliation(s)
- Barbara Infante
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto Luigi 251, 71122 Foggia, Italy; (B.I.); (S.L.); (D.T.); (G.S.)
| | - Michele Rossini
- Clinical Pathology Unit and Center of Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto, 71122 Foggia, Italy; (M.R.); (G.S.N.); (E.R.)
| | - Serena Leo
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto Luigi 251, 71122 Foggia, Italy; (B.I.); (S.L.); (D.T.); (G.S.)
| | - Dario Troise
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto Luigi 251, 71122 Foggia, Italy; (B.I.); (S.L.); (D.T.); (G.S.)
| | - Giuseppe Stefano Netti
- Clinical Pathology Unit and Center of Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto, 71122 Foggia, Italy; (M.R.); (G.S.N.); (E.R.)
| | - Elena Ranieri
- Clinical Pathology Unit and Center of Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto, 71122 Foggia, Italy; (M.R.); (G.S.N.); (E.R.)
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy;
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto Luigi 251, 71122 Foggia, Italy; (B.I.); (S.L.); (D.T.); (G.S.)
- Correspondence: ; Tel.: +39-0881732610; Fax: +39-0881736001
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto Luigi 251, 71122 Foggia, Italy; (B.I.); (S.L.); (D.T.); (G.S.)
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Nunius C, Büttner-Herold M, Bertz S, Schiffer M, Buchholz B. Isolated thrombotic microangiopathy of the small intestine in a patient with atypical hemolytic uremic syndrome - a case report. BMC Nephrol 2020; 21:104. [PMID: 32204691 PMCID: PMC7092568 DOI: 10.1186/s12882-020-01766-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 03/13/2020] [Indexed: 01/04/2023] Open
Abstract
Background Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by systemic thrombotic microangiopathy (TMA) reflected by hemolysis, anemia, thrombocytopenia and systemic organ injury. The optimal management of aHUS-patients when undergoing kidney transplantation to prevent recurrence in the allograft is eculizumab, an approved recombinant antibody targeting human complement component C5. Case presentation A 39 year-old woman presented with severe abdominal pain, diarrhea and emesis for 3 days. In her past medical history she had experienced an episode of aHUS leading to end stage renal disease (ESRD) in 2007 and a genetic workup revealed a heterozygous mutation in the membrane cofactor protein gene. In 2014 she underwent cadaveric kidney transplantation. Four years later she had to go back on hemodialysis due to allograft failure following a severe systemic cytomegalovirus infection resulting in transplant failure. At presentation she still received calcineurin-inhibitor therapy and reported subfebrile temperatures and pain projecting over the transplant prior to the current symptoms. A contrast enhanced CT-scan of the abdomen revealed inflammatory wall thickening of the small intestine. Diagnostic endoscopy discovered fresh blood in the small intestine without a clear source of bleeding. Histopathology of the small intestine biopsies showed severe thrombotic microangiopathy. Of note, the patient persistently had no signs of systemic hemolysis. Since the TMA of the small intestine was most likely due to aHUS, eculizumab treatment was initiated which abolished the symptoms. Conclusion Here we report a patient with thrombotic microangiopathy with predominant manifestation in a single organ, the small intestine, due to aHUS with absence of systemic signs and symptoms. aHUS patients usually require a secondary trigger for the disease to manifest. In this case, the trigger may be attributed to the dysfunctional renal transplant, which was subsequently explanted. Histology of the explanted kidney showed severe inflammation due to purulent nephritis and signs of cellular rejection. After nephrectomy, we continued eculizumab therapy until the patient completely recovered. No signs of TMA recurred after discontinuation of eculizumab, further supporting the concept of the renal transplant as the main trigger of TMA of the small intestine in our patient.
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Affiliation(s)
- Christoph Nunius
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg, 18, Erlangen, Germany.
| | - Maike Büttner-Herold
- Department of Nephropathology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Simone Bertz
- Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Mario Schiffer
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg, 18, Erlangen, Germany
| | - Bjoern Buchholz
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg, 18, Erlangen, Germany
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Mukherjee AA, Kandhare AD, Bodhankar SL. Evaluation of health-related quality of life in hemolytic uraemic syndrome patients treated with eculizumab: a systematic evaluation on basis of EMPRO. Ren Fail 2018; 40:107-118. [PMID: 29363392 PMCID: PMC6014301 DOI: 10.1080/0886022x.2018.1427110] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 10/07/2017] [Accepted: 12/14/2017] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Hemolytic uraemic syndrome (HUS) is progressive renal failure disease and determination of their quality of life (QoL) on the basis of patient-reported outcomes (PROs) are becoming increasingly important in the economic evaluations for its treatment with eculizumab (ECU). AIM To perform the systematic evaluation of QoL in HUS patients treated with ECU on the basis of Evaluating Measures of Patient Reported Outcomes (EMPRO) tool. MATERIALS AND METHODS A systematic review was conducted in PubMed, EMBASE, the Cochrane Library, CINAHL and Google Scholar till September 2016 by two independent researchers. Each identified instrument was evaluated for its quality of performance by using the EMPRO tool for its overall score and seven attribute specific scores (range 0-100, worst to best). RESULTS Five different PROs instruments were identified from 10 articles (n = 112) which showed eculizumab significantly improves health-related quality of life (HRQOL) in atypical HUS (aHUS) patients. Amongst five instruments viz. EuroQol five dimensions questionnaire (EQ-5 D), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Headache Impact Test-6 (HIT-6), 36-Item Short Form Health Survey (SF-36) and Visual Analogue Scale (VAS), the overall EMPRO score was higher for VAS (73.83) and EQ-5 D (73.81). Whereas, FACIT-F and HIT- 6 were just able to meet the minimal threshold of EMPRO scoring (50.24 and 59.09, respectively). CONCLUSIONS Evidence from present investigation support that eculizumab significantly improves HRQoL in patients with aHUS furthermore, EQ-5 D and VAS instrument should be recommended for assessing HRQoL in them. However, selection of PRO instrument for determination of QoL in HUS entirely depend upon the study requirements.
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Affiliation(s)
| | - Amit D. Kandhare
- Department of Pharmacology, Poona College of Pharmacy, Pune, India
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Atypical hemolytic uremic syndrome: Review of clinical presentation, diagnosis and management. J Immunol Methods 2018; 461:15-22. [PMID: 30031798 DOI: 10.1016/j.jim.2018.07.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 05/30/2018] [Accepted: 07/18/2018] [Indexed: 12/12/2022]
Abstract
Thrombotic microangiopathies (TMA) are a class of disorders characterized by microangiopathic hemolytic anemia, non-immune thrombocytopenia, and organ dysfunction. One type of TMA is atypical hemolytic uremic syndrome (aHUS) a disorder caused by hyper-activation of the alternative complement pathway due to over activation of C3 convertases and loss of complement regulatory mechanisms. The pathophysiological mechanism of aHUS involves increased continuous spontaneous hydrolysis of C3 to C3b which leads to tissue deposition of C3b, the membrane attack complex formation and subsequent tissue injury. The underlying susceptibility factors to aHUS include acquired autoantibodies or germline mutations in complement proteins or their regulators. Currently there are no clear diagnostic criteria for aHUS. Diagnosis involves ruling out other causes of TMA and incorporating complement serologic and genetic data. TPE has been used to treat aHUS; however, clinical improvement in these patents is far less than in patients with thrombotic thrombocytopenic purpura. Furthermore, there is a higher rate of progression to end stage renal disease with almost half of patients progressing despite TPE. For those, another option for treatment is eculizumab, a monoclonal antibody that blocks complement C5. Eculizumab has proven effective in aHUS and dramatically changed the prognosis of this syndrome. In this review the clinical presentation, diagnosis and management of aHUS are highlighted with three clinical cases.
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Abstract
Thrombotic microangiopathy can manifest in a diverse range of diseases and is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and organ injury, including AKI. It can be associated with significant morbidity and mortality, but a systematic approach to investigation and prompt initiation of supportive management and, in some cases, effective specific treatment can result in good outcomes. This review considers the classification, pathology, epidemiology, characteristics, and pathogenesis of the thrombotic microangiopathies, and outlines a pragmatic approach to diagnosis and management.
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Affiliation(s)
- Vicky Brocklebank
- National Renal Complement Therapeutics Centre, Newcastle upon Tyne, Hospitals National Health Service Foundation Trust, Newcastle upon Tyne, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; and
| | - Katrina M. Wood
- Department of Cellular Pathology, Newcastle upon Tyne Hospitals National Health Service Foundation Trust, Newcastle upon Tyne, UK
| | - David Kavanagh
- National Renal Complement Therapeutics Centre, Newcastle upon Tyne, Hospitals National Health Service Foundation Trust, Newcastle upon Tyne, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; and
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11
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Wong EKS, Kavanagh D. Diseases of complement dysregulation-an overview. Semin Immunopathol 2018; 40:49-64. [PMID: 29327071 PMCID: PMC5794843 DOI: 10.1007/s00281-017-0663-8] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Accepted: 11/01/2017] [Indexed: 02/07/2023]
Abstract
Atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), and paroxysmal nocturnal hemoglobinuria (PNH) are prototypical disorders of complement dysregulation. Although complement overactivation is common to all, cell surface alternative pathway dysregulation (aHUS), fluid phase alternative pathway dysregulation (C3G), or terminal pathway dysregulation (PNH) predominates resulting in the very different phenotypes seen in these diseases. The mechanism underlying the dysregulation also varies with predominant acquired autoimmune (C3G), somatic mutations (PNH), or inherited germline mutations (aHUS) predisposing to disease. Eculizumab has revolutionized the treatment of PNH and aHUS although has been less successful in C3G. With the next generation of complement therapeutic in late stage development, these archetypal complement diseases will provide the initial targets.
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Affiliation(s)
- Edwin K S Wong
- The National Renal Complement Therapeutics Centre, aHUS Service, Building 26, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK.,Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - David Kavanagh
- The National Renal Complement Therapeutics Centre, aHUS Service, Building 26, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK. .,Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
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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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13
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Abstract
Atypical hemolytic-uremic syndrome (HUS) is a rare life-threatening disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, and ischemic injury to organs, especially the kidneys. Microvascular injury and thrombosis are the dominant histologic findings. Complement activation through the alternative pathway plays a critical role in the pathogenesis of atypical HUS. Genetic abnormalities involving complement regulatory proteins and complement components form the molecular basis for complement activation. Endothelial cell dysfunction, probably because of the effects of complement activation, is an intermediate stage in the pathophysiologic cascade. Atypical HUS has a grave prognosis. Although mortality approaches 25% during the acute phase, end-stage renal disease develops in nearly half of patients within a year. Atypical HUS has a high recurrence rate after renal transplantation, and recurrent disease often leads to graft loss. Plasma therapy in the form of plasma exchange or infusion has remained the standard treatment for atypical HUS. However, many patients do not respond to plasma therapy and some require prolonged treatment. Approved by the Food and Drug Administration in the treatment of atypical HUS, eculizumab is a humanized monoclonal antibody that blocks cleavage of complement C5 into biologically active mediators of inflammation and cytolysis. Although case reports have shown the efficacy of eculizumab, randomized clinical trials are lacking. Therapeutic strategies targeting endothelial cells have demonstrated promising results in experimental settings. Therefore, inhibitors of angiotensin-converting enzyme, HMG-CoA reductase, and xanthine oxidase as well as antioxidants, such as ascorbic acid, may have salutary effects in patients with atypical HUS.
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Sampson MG. Actualizing the Benefits of Genomic Discovery in Pediatric Nephrology. J Pediatr Genet 2015; 5:69-75. [PMID: 27617144 DOI: 10.1055/s-0035-1557113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2014] [Accepted: 01/19/2015] [Indexed: 01/13/2023]
Abstract
The discovery of genetic variation associated with pediatric kidney disease has shed light on the biology underlying these conditions and, in some cases, has improved our clinical management of patients. We are challenged to continue the momentum of the genomic era in pediatric nephrology by identifying novel disease-associated genetic variation and translating these discoveries into clinical applications. This article reviews the diverse forms of genetic architecture that have been found to be associated with kidney diseases and traits. These include rare, fully penetrant variants responsible for Mendelian forms of disease, copy number variants, and more common variants associated with increased risk of disease. These discoveries have provided us with a greater understanding of the molecular mechanisms underlying these conditions and highlighted key pathways for potential intervention. In a number of areas, the identification of rare, fully penetrant variants is immediately clinically relevant, whether in regard to diagnostic testing, prediction of outcomes, or choice of therapies and interventions. This article discusses limitations in the deterministic view of rare, putatively causal mutations, a challenge increasing in importance as sequencing expands to many more genes and patients. This article also focusses on common genetic variants, using those found to be associated with focal segmental glomerulosclerosis in African-Americans, IgA nephropathy, chronic kidney disease (CKD), and estimated glomerular filtration rate (eGFR) as examples. Identifying common genetic variants associated with disease will complement other areas of genomic inquiry, lead to a greater biological understanding of disease, and will benefit pediatric nephrology patients.
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Affiliation(s)
- Matthew G Sampson
- Division of Pediatric Nephrology, Department of Pediatrics and Communicable Diseases, University of Michigan School of Medicine, Ann Arbor, Michigan, United States
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15
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Brocklebank V, Kavanagh D. Protecting the kidney from complement: atypical haemolytic uraemic syndrome. Clin Med (Lond) 2014; 14 Suppl 6:s89-94. [PMID: 25468928 DOI: 10.7861/clinmedicine.14-6-s89] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Atypical haemolytic uraemic syndrome is a thrombotic microangiopathy with a predominant renal phenotype. Research developments in the last 15 years have led to the elucidation of the role of complement over activation in the pathogenesis of the disease. This was to lead to the successful introduction of targeted pharmacological therapy, in the form of the complement inhibitor, eculizumab.
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Affiliation(s)
| | - David Kavanagh
- The Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK
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Asif A, Vachharajani T, Salman L, Nayer A. A Simplified Approach to the Diagnosis of Atypical HUS: Clinical Considerations and Practical Implications. ACTA ACUST UNITED AC 2014. [DOI: 10.2174/1874303x01407010091] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Although rare, atypical hemolytic-uremic syndrome (aHUS) carries a high morbidity and mortality. Widespread microvascular thrombosis, thrombocytopenia and microangiopathic hemolytic anemia are the hallmark of aHUS. Virtually any organ (particularly the kidney) can be a target for the devastating effects of this syndrome. Uncontrolled activation of the alternative pathway of the complement system lies at the heart of the pathogenesis of aHUS. While significant advances have been made in our understanding of aHUS, establishing timely diagnosis of this syndrome has been challenging. This, in part, is due to the absence of a sensitive and specific diagnostic test and a relatively lack of our familiarity with the syndrome. With the recent success and approval of a humanized monoclonal antibody (eculizumab) in the treatment of aHUS, prompt and accurate diagnosis is of paramount importance to limit the target organ injury. This article presents a simplified approach to establishing the diagnosis of aHUS.
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Cugno M, Gualtierotti R, Possenti I, Testa S, Tel F, Griffini S, Grovetti E, Tedeschi S, Salardi S, Cresseri D, Messa P, Ardissino G. Complement functional tests for monitoring eculizumab treatment in patients with atypical hemolytic uremic syndrome. J Thromb Haemost 2014; 12:1440-8. [PMID: 24853860 DOI: 10.1111/jth.12615] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 05/14/2014] [Indexed: 11/29/2022]
Abstract
BACKGROUND Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy characterized by hemolysis, platelet consumption, and renal injury. Eculizumab, a mAb that blocks complement activity, has been successfully used in aHUS. OBJECTIVES To optimize eculizumab therapy in aHUS patients by monitoring complement functional tests and markers of disease activity. PATIENTS/METHODS We studied 18 patients with aHUS (10 males; eight females; age range, 2-40 years) treated with eculizumab to induce and/or maintain disease remission. Patients were followed up for a cumulative observation period of 160 months, during which blood samples were obtained at various time intervals to measure complement activity (Wieslab for the classical, alternative and mannose-binding lectin complement pathways) and the parameters of disease activity (haptoglobin and lactate dehydrogenase serum levels, and platelet count). The intravenous eculizumab doses of 12-33 mg kg(-1) were initially administered every week, with the interval between doses being gradually extended to 2 weeks, 3 weeks and 4 weeks on the basis of strict laboratory and clinical control. RESULTS Complement activity was normal before eculizumab treatment, regardless of the state of the disease (activity or remission). It was completely suppressed 1 week, 2 weeks and 3 weeks after the last eculizumab infusion (mean values ± standard deviation: 1% ± 1% to 3% ± 5% for both the classical and alternative pathways; P = 0.0001 vs. baseline), and partially suppressed after 4 weeks (22% ± 26% and 16% ± 27%; P = 0.0001 vs. baseline). The increase in the time interval between eculizumab infusions did not change disease activity markers. CONCLUSIONS Monitoring complement tests can allow a safe reduction in the frequency of eculizumab administration in aHUS while keeping the disease in remission.
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Affiliation(s)
- M Cugno
- Medicina Interna, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
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Abstract
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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Abstract
PURPOSE OF REVIEW The diagnosis of thrombotic microangiopathy (TMA) is complex and often difficult. This review provides an approach to the diagnosis with emphasis on recent relevant developments. RECENT FINDINGS There is increasing evidence that most cases of recurrent TMA in renal allografts are secondary to mutations in genes encoding complement regulatory factors and complement components, such as factor H, factor I, membrane cofactor protein, C3, and others. Genetic work-up for these potential complement abnormalities is now available and recommended. Another important cause for recurrent TMA is the presence of autoantibodies, such as antibodies to factor H and antiphospholipid antibodies. De-novo TMA is much more common than recurrent TMA in renal allografts. De-novo TMA can be secondary to calcineurin inhibitor treatment, mammalian target of rapamycin inhibitor treatment, but frequently also to antibody-mediated rejection and less commonly to infections. Systemic signs of TMA are often absent, and the gold standard for diagnosis is the renal allograft biopsy. Unfortunately, diagnostic criteria for TMA are somewhat subjective, and the biopsy provides limited information regarding the exact underlying cause. SUMMARY TMA is a serious complication of renal transplantation, usually with poor outcome. However, with improving understanding of underlying pathogeneses, more effective disease-specific therapeutic interventions can be designed. Appropriate treatment depends on the correct diagnosis, which relies primarily on renal allograft biopsy. Standardization of pathologic criteria and introduction of new molecular testing methods in renal biopsy specimens hopefully will improve diagnostic accuracy.
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Affiliation(s)
- Tibor Nadasdy
- Department of Pathology, The Ohio State University, Columbus, Ohio, USA
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Kaplan BS, Ruebner RL, Spinale JM, Copelovitch L. Current treatment of atypical hemolytic uremic syndrome. Intractable Rare Dis Res 2014; 3:34-45. [PMID: 25343125 PMCID: PMC4204535 DOI: 10.5582/irdr.2014.01001] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Revised: 02/17/2014] [Accepted: 02/23/2014] [Indexed: 12/25/2022] Open
Abstract
Tremendous advances have been made in understanding the pathogenesis of atypical Hemolytic Uremic Syndrome (aHUS), an extremely rare disease. Insights into the molecular biology of aHUS resulted in rapid advances in treatment with eculizumab (Soliris(®), Alexion Pharmaceuticals Inc.). Historically, aHUS was associated with very high rates of mortality and morbidity. Prior therapies included plasma therapy and/or liver transplantation. Although often life saving, these were imperfect and had many complications. We review the conditions included under the rubric of aHUS: S. pneumoniae HUS (SpHUS), inborn errors of metabolism, and disorders of complement regulation, emphasizing their differences and similarities. We focus on the clinical features, diagnosis, and pathogenesis, and treatment of aHUS that results from mutations in genes encoding alternative complement regulators, SpHUS and HUS associated with inborn errors of metabolism. Mutations in complement genes, or antibodies to their protein products, result in unregulated activity of the alternate complement pathway, endothelial injury, and thrombotic microangiopathy (TMA). Eculizumab is a humanized monoclonal antibody that inhibits the production of the terminal complement components C5a and the membrane attack complex (C5b-9) by binding to complement protein C5a. This blocks the proinflammatory and cytolytic effects of terminal complement activation. Eculizumab use has been reported in many case reports, and retrospective and prospective clinical trials in aHUS. There have been few serious side effects and no reports of tachphylaxis or drug resistance. The results are very encouraging and eculizumab is now recognized as the treatment of choice for aHUS.
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Affiliation(s)
- Bernard S. Kaplan
- Division of Pediatric Nephrology, Department of Pediatrics, The Children's Hospital of Philadelphia, and The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Address correspondence to: Dr. Bernard S. Kaplan, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA. E-mail:
| | - Rebecca L. Ruebner
- Division of Pediatric Nephrology, Department of Pediatrics, The Children's Hospital of Philadelphia, and The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Joann M. Spinale
- Division of Pediatric Nephrology, Department of Pediatrics, The Children's Hospital of Philadelphia, and The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Lawrence Copelovitch
- Division of Pediatric Nephrology, Department of Pediatrics, The Children's Hospital of Philadelphia, and The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania, USA
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21
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Brocklebank V, Wong EKS, Fielding R, Goodship THJ, Kavanagh D. Atypical haemolytic uraemic syndrome associated with a CD46 mutation triggered by Shigella flexneri.. Clin Kidney J 2014; 7:286-288. [PMID: 24944786 PMCID: PMC4038258 DOI: 10.1093/ckj/sfu032] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2014] [Accepted: 03/13/2014] [Indexed: 11/29/2022] Open
Abstract
We present a case of haemolytic uraemic syndrome (HUS) triggered by Shigella flexneri. Of the Shigella species, only S. dysenteriae type 1 is said to produce Shiga toxin and consequently cause HUS. Investigation of the complement system in this patient revealed a CD46 mutation. In individuals with mutations in complement genes incomplete penetrance of atypical HUS (aHUS) is seen, suggesting that a trigger, such as infection, is required for disease to manifest. In an era of complement modulatory therapy for aHUS it is important to be alert to unusual presentations of diarrhoeal-associated disease.
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Affiliation(s)
| | - Edwin K S Wong
- The Institute of Genetic Medicine , Newcastle University , Newcastle upon Tyne , UK
| | - Rick Fielding
- Renal Services Centre , Freeman Hospital , Newcastle upon Tyne , UK
| | - Timothy H J Goodship
- Renal Services Centre , Freeman Hospital , Newcastle upon Tyne , UK ; The Institute of Genetic Medicine , Newcastle University , Newcastle upon Tyne , UK
| | - David Kavanagh
- Renal Services Centre , Freeman Hospital , Newcastle upon Tyne , UK ; The Institute of Genetic Medicine , Newcastle University , Newcastle upon Tyne , UK
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Saland J. Liver-kidney transplantation to cure atypical HUS: still an option post-eculizumab? Pediatr Nephrol 2014; 29:329-32. [PMID: 24362724 DOI: 10.1007/s00467-013-2722-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Revised: 11/19/2013] [Accepted: 12/03/2013] [Indexed: 02/06/2023]
Abstract
Patients with end-stage renal disease (ESRD) due to atypical HUS (aHUS) now have several potential options that can enable successful kidney transplantation. This editorial addresses these options by considering key factors that are important when making an individual treatment decision.
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Affiliation(s)
- Jeffrey Saland
- Mount Sinai Medical School, 1 Gustave L. Levy Pl, New York, NY, 10029, USA,
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Abstract
Immunosuppressive therapy in pediatrics continues to evolve. Over the past decade, newer immunosuppressive agents have been introduced into adult and pediatric transplant patients with the goal of improving patient and allograft survival. Unfortunately, large-scale randomized clinical trials are not commonly performed in children. The purpose of this review is to discuss the newer immunosuppressive agents available for induction therapy, maintenance immunosuppression, and the treatment of rejection.
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Affiliation(s)
- Christina Nguyen
- Division of Pediatric Nephrology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States
| | - Ron Shapiro
- Division of Transplant Surgery, UPMC Thomas E. Starzl Transplantation Institute, Pittsburgh, PA, United States
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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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Neidich AB, Neidich EM, Lee A, Nicoletta J, Rohrer RJ, Milner LS, Cooper JT. Novel use of intravenous immunoglobulin G in complement factor H missense mutation: a case report. Prog Transplant 2013; 23:213-6. [PMID: 23996939 DOI: 10.7182/pit2013151] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
A white girl presented at 8 months of age with thrombotic microangiopathy, followed by recurrent episodes of renal dysfunction, hemolysis, and thrombocytopenia, compatible with atypical hemolytic uremic syndrome. The episodes of the syndrome were treated by a combination of infusions of fresh frozen plasma, plasmapheresis, and continuous venovenous hemodialysis. Interval resolution occurred between episodes. At 2 years of age, prophylactic infusions of fresh frozen plasma were started between relapses, but this proved to be poorly protective; however, introduction of prophylactic intravenous gamma globulin at age 3.5 years resulted in prolonged remission (42 months). Serum levels of the third and fourth components of complement, total hemolytic complement, and complement factor H were normal. Results of the third component functional assay were low before and normalized after the start of immunoglobulin G prophylaxis. A missense mutation of complement factor H was identified. At 6 years of age, the patient underwent bilateral native nephrectomy and started long-term peritoneal dialysis, followed by a combined liver-kidney transplant at age 8 years. Four and a half years after transplant, she has excellent renal and liver graft function without recurrence of atypical hemolytic uremic syndrome.
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Rathbone J, Kaltenthaler E, Richards A, Tappenden P, Bessey A, Cantrell A. A systematic review of eculizumab for atypical haemolytic uraemic syndrome (aHUS). BMJ Open 2013; 3:e003573. [PMID: 24189082 PMCID: PMC3822313 DOI: 10.1136/bmjopen-2013-003573] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE To determine the efficacy and safety of eculizumab for patients with atypical haemolytic uraemic syndrome (aHUS), compared with current treatment options. DESIGN A systematic review was performed according to the general principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. All study designs were included, except case histories. PARTICIPANTS All patients diagnosed with aHUS were included; no age restrictions were used. INTERVENTIONS Eculizumab compared with current treatment options. IDENTIFICATION OF STUDIES 12 databases were searched. Additional searches were performed through the Food and Drug Administration (FDA) and the Electronic Medicines Compendium websites, Google internet searches and contacting clinical experts. Reference lists of relevant articles were checked for additional studies. RESULTS 2 small, uncontrolled prospective multinational, multicentre studies and one small uncontrolled multinational, multicentre retrospective study were included. No meta-analyses were performed. Compared with baseline measures, thrombotic microangiopathy event-free status was achieved in 84% of patients in the prospective studies. Adverse events, as documented by enrolling investigators were frequent, with upper-respiratory tract infection affecting a third of patients. No deaths or episodes of meningitis or meningococcal septicaemia occurred in the prospective studies. Results of the study extension phases up to 114 weeks indicate that the benefits of the treatment are sustained. CONCLUSIONS Eculizumab is clinically effective for the treatment of aHUS. Further research is needed to evaluate eculizumab, ideally using patient-related clinical outcomes. If randomised studies are not feasible, study investigators should ensure that the threat of bias is minimised in future studies of eculizumab with respect to the reporting of patient recruitment and selection.
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Affiliation(s)
- John Rathbone
- School of Health and Related Research, University of Sheffield, Sheffield, UK
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27
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Xie L, Nester CM, Reed AI, Zhang Y, Smith RJ, Thomas CP. Tailored eculizumab therapy in the management of complement factor H-mediated atypical hemolytic uremic syndrome in an adult kidney transplant recipient: a case report. Transplant Proc 2013. [PMID: 23195022 DOI: 10.1016/j.transproceed.2012.07.141] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Atypical hemolytic uremic syndrome (aHUS) is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury (AKI) which frequently progresses to end-stage renal disease (ESRD). In 50% of affected patients, mutations in complement regulatory proteins cause inappropriate complement activation with endothelial injury. Complement factor H (CFH) mutations cause 25% of aHUS cases; these patients have an 80% recurrence risk after kidney transplantation. Eculizumab, an anti-C5 antibody, is effective in limiting hemolysis episodes in patients with aHUS, but less is known about preventing recurrence after kidney transplantation. Herein we report the use of prophylactic eculizumab in an adult with aHUS who underwent kidney transplantation. A 31-year-old female presented with aHUS and progressive AKI associated with low complement 3 level leading to ESRD despite plasmapheresis and corticosteroids. She had a heterozygous nonsense mutation in CFH and reduced plasma CFH levels. She was given preoperative plasmapheresis and eculizumab and underwent living unrelated renal transplantation. Postoperatively, eculizumab was dosed to achieve low functional complement 5 levels and low soluble membrane attack complex levels and she has maintained excellent graft function without aHUS recurrence. We propose that eculizumab with titrated dosing should be used in CFH-mediated aHUS patients who are at a high risk of recurrence.
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Affiliation(s)
- L Xie
- Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
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Kaplan BS, Ruebner RL, Copelovitch L. Eculizumab treatment of atypical hemolytic uremic syndrome. Expert Opin Orphan Drugs 2012. [DOI: 10.1080/21678707.2013.750579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Kalluri HV, Hardinger KL. Current state of renal transplant immunosuppression: Present and future. World J Transplant 2012; 2:51-68. [PMID: 24175197 PMCID: PMC3782235 DOI: 10.5500/wjt.v2.i4.51] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2011] [Revised: 11/23/2011] [Accepted: 06/30/2012] [Indexed: 02/05/2023] Open
Abstract
For kidney transplant recipients, immunosuppression commonly consists of combination treatment with a calcineurin inhibitor, an antiproliferative agent and a corticosteroid. Many medical centers use a sequential immunosuppression regimen where an induction agent, either an anti-thymocyte globulin or interleukin-2 receptor antibody, is given at the time of transplantation to prevent early acute rejection which is then followed by a triple immunosuppressive maintenance regimen. Very low rejection rates have been achieved at many transplant centers using combinations of these agents in a variety of protocols. Yet, a large number of recipients suffer chronic allograft injury and adverse events associated with drug therapy. Regimens designed to limit or eliminate calcineurin inhibitors and/or corticosteroid use are actively being pursued. An ideal immunosuppressive regimen limits toxicity and prolongs the functional life of the graft. This article contains a critical analysis of clinical data on currently available immunosuppressive strategies and an overview of therapeutic moieties in development.
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Affiliation(s)
- Hari Varun Kalluri
- Hari Varun Kalluri, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15260, United States
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Kavanagh D, Anderson HE. Interpretation of genetic variants of uncertain significance in atypical hemolytic uremic syndrome. Kidney Int 2012; 81:11-3. [PMID: 22170528 DOI: 10.1038/ki.2011.330] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Mutations in complement proteins predispose to atypical hemolytic uremic syndrome (aHUS). Mutation screening in aHUS is challenging, because most of the disease-associated mutations are individually rare, and a significant proportion of variants consist of missense mutations of unknown significance. The definitive interpretation of a variant of unknown significance (VUS) is often dependent on a reliable functional assay too time-consuming to be used in a diagnostic screening service. Allied research groups have analyzed these VUSs in aHUS.
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Affiliation(s)
- David Kavanagh
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
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Gabardi S, Halloran PF, Friedewald J. Managing risk in developing transplant immunosuppressive agents: the new regulatory environment. Am J Transplant 2011; 11:1803-9. [PMID: 21827622 DOI: 10.1111/j.1600-6143.2011.03653.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Recent adverse experience with a number of medications after their approval, including rofecoxib, erythropoietin and rosiglitazone, has led to an increased focus on safety in drug development in the postmarketing setting. The result was implementation of new measures to address perceived deficits in the system for drug approval and postmarketing safety. The resulting legislation introduced risk evaluation and mitigation strategies (REMS) and postmarketing requirements (PMRs). Although these initiatives have the potential to improve patient outcomes, many healthcare practitioners are not yet familiar with REMS or PMRs or may have misconceptions regarding their goals and limitations. REMS is a program to manage known or potential serious risks associated with pharmaceutical products and is designed to ensure that the benefits of using a particular product outweigh the risks. Although the concepts underlying REMS and PMRs are not novel, the FDA now has legal authority to enforce such measures as part of the drug approval process. This article outlines the objectives and limitations of REMS and PMRs, with a focus on how these regulatory measures may impact the clinical specialty of transplantation. The article also briefly describes efforts to address aspects of drug safety less amenable to management through REMS and PMRs.
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Affiliation(s)
- S Gabardi
- Department of Transplant Surgery and Pharmacy Services and Renal Division, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA, USA.
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Boyer O, Niaudet P. Hemolytic uremic syndrome: new developments in pathogenesis and treatment. Int J Nephrol 2011; 2011:908407. [PMID: 21876803 PMCID: PMC3159990 DOI: 10.4061/2011/908407] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2011] [Accepted: 06/14/2011] [Indexed: 12/27/2022] Open
Abstract
Hemolytic uremic syndrome is defined by the characteristic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. In children, most cases of HUS are caused by Shiga-toxin-producing bacteria, especially Escherichia coli O157:H7. Common vehicles of transmission include ground beef, unpasteurized milk, and municipal or swimming water. Shiga-toxin-associated HUS is a main cause of acute renal failure in young children. Management remains supportive as there is at present no specific therapy to ameliorate the prognosis. Immediate outcome is most often favourable but long-term renal sequelae are frequent due to nephron loss. Atypical HUS represents 5% of cases. In the past 15 years, mutations in complement regulators of the alternative pathway have been identified in almost 60% of cases, leading to excessive complement activation. The disease has a relapsing course and more than half of the patients either die or progress to end-stage renal failure. Recurrence after renal transplantation is frequent.
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Affiliation(s)
- Olivia Boyer
- Service de Néphrologie Pédiatrique, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France
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Weitz M, Amon O, Bassler D, Koenigsrainer A, Nadalin S. Prophylactic eculizumab prior to kidney transplantation for atypical hemolytic uremic syndrome. Pediatr Nephrol 2011; 26:1325-9. [PMID: 21556717 DOI: 10.1007/s00467-011-1879-9] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2010] [Revised: 03/21/2011] [Accepted: 03/21/2011] [Indexed: 12/14/2022]
Abstract
Atypical hemolytic uremic syndrome (aHUS) in childhood is a rare disease associated with high morbidity and mortality. Most cases progress to end-stage renal failure. In approximately 50% of affected patients, mutations in genes encoding complement proteins are causative of the impairment in the regulation of the complement alternative pathway. This leads to deficient host cell protection and inappropriate complement activation on platelets and endothelial cells, particularly in the kidneys. Complement factor H (FH) heterozygosity induces unregulated activation of the membrane attack complex (MAC) C5b-9. Present therapeutic strategies for aHUS include lifelong plasmapheresis and renal dialysis. Unfortunately, kidney transplantation is frequently an unsatisfactory intervention due to the high rate of post-transplantation HUS recurrence, particularly in patients with FH mutation. Combined liver-kidney transplantation is also associated with poor outcome, mostly as a result of premature liver failure secondary to uncontrolled complement activation. Eculizumab is a complement C5 antibody that inhibits complement factor 5a (C5a) and the formation of the MAC. Thus, this antibody may be a promising new agent for patients with an aHUS undergoing kidney transplantation. We present the first case of a young patient with aHUS who received eculizumab as prophylactic treatment prior to a successful kidney transplantation.
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Affiliation(s)
- Marcus Weitz
- University Children's Hospital Tuebingen, Tuebingen, Germany.
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Gabardi S. Understanding Risk Evaluation and Mitigation Strategies in Organ Transplantation. Pharmacotherapy 2011; 31:714-22. [DOI: 10.1592/phco.31.7.714] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease that presents with protean manifestations. Clinical and laboratory investigation over the past 25 years has uncovered most of the basic science underpinnings of PNH and has led to the development of a highly effective targeted therapy. PNH originates from a multipotent hematopoietic stem cell (HSC) that acquires a somatic mutation in a gene called phosphatidylinositol glycan anchor biosynthesis, class A (PIG-A). The PIG-A gene is required for the first step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Failure to synthesize GPI anchors leads to an absence of all proteins that utilize GPI to attach to the plasma membrane. Two GPI-anchor proteins, CD55 and CD59, are complement regulatory proteins; their absence on the surface of PNH cells leads to complement-mediated hemolysis. The release of free hemoglobin leads to scavenging of nitric oxide and contributes to many clinical manifestations, including esophageal spasm, fatigue, and possibly thrombosis. Aerolysin is a pore-forming toxin that binds GPI-anchored proteins and kills normal cells, but not PNH cells. A fluorescinated aerolysin variant (FLAER) binds GPI-anchor and serves as a novel reagent diagnosing PNH. Eculizumab, a humanized monoclonal antibody against C5, is the first effective drug therapy for PNH.
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Affiliation(s)
- Jeffrey J Pu
- Division of Hematology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
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Roumenina LT, Loirat C, Dragon-Durey MA, Halbwachs-Mecarelli L, Sautes-Fridman C, Fremeaux-Bacchi V. Alternative complement pathway assessment in patients with atypical HUS. J Immunol Methods 2011; 365:8-26. [PMID: 21215749 DOI: 10.1016/j.jim.2010.12.020] [Citation(s) in RCA: 116] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2010] [Revised: 10/31/2010] [Accepted: 12/30/2010] [Indexed: 01/02/2023]
Abstract
The atypical Hemolytic Uremic Syndrome (aHUS) is a rare thrombotic microangiopathy leading to end stage renal disease in approximately 60% of patients. Over the last decade, a clear link has been demonstrated between this disease and defective complement regulation. The hallmark of the aHUS is the association with mutations in complement alternative pathway genes. Endothelial damage is related to complement dysregulation, but the exact mechanism is just starting to be elucidated. Screening for and characterization of mutations in the components of the C3 convertase (C3 and FB) or its regulators (FH, FI, MCP, and Thrombomodulin) or anti-FH antibodies has become an indispensable part of the disease's diagnostic. This review will initially summarize current knowledge on the understanding of complement activation and regulation, followed by a description on the genetic analysis as well as the methods used for complement protein quantification. Another part of this review will focus on the mechanisms of action of aHUS-associated mutations. We will emphasize on when and why some mutations lead to protein deficiency, while others result in - to dysfunctional but normally expressed proteins. Finally, we will discuss how the therapy of aHUS patients can be modified according to the functional consequences of each particular genetic defect.
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Kavanagh D, Goodship THJ. Atypical hemolytic uremic syndrome, genetic basis, and clinical manifestations. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2011; 2011:15-20. [PMID: 22160007 DOI: 10.1182/asheducation-2011.1.15] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
Atypical hemolytic uremic syndrome (aHUS) is now well recognized to be a disease characterized by excessive complement activation in the microvasculature. In both the familial and sporadic forms, inherited and acquired abnormalities affecting components of the alternative complement pathway are found in ~ 60% of patients. These include mutations in the genes encoding both complement regulators (factor H, factor I, membrane cofactor protein, and thrombomodulin) and activators (factors B and C3) and autoantibodies against factor H. Multiple hits are necessary for the disease to manifest, including a trigger, mutations, and at-risk haplotypes in complement genes. The prognosis for aHUS is poor, with most patients developing end-stage renal failure. Renal transplantation in most patients also has a poor prognosis, with frequent loss of the allograft to recurrent disease. However, improving results with combined liver-kidney transplantation and the advent of complement inhibitors such as eculizumab offer hope that the prognosis for aHUS will improve in future years.
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Affiliation(s)
- David Kavanagh
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
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Abstract
Central to the pathogenesis of atypical hemolytic uremic syndrome (aHUS) is over-activation of the alternative pathway of complement. Following the initial discovery of mutations in the complement regulatory protein, factor H, mutations have been described in factor I, membrane cofactor protein and thrombomodulin, which also result in decreased complement regulation. Autoantibodies to factor H have also been reported to impair complement regulation in aHUS. More recently, gain of function mutations in the complement components C3 and Factor B have been seen. This review focuses on the genetic causes of aHUS, their functional consequences, and clinical effect.
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