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1.
Volokhina E Westra D Xue X Gros P van de Kar N van den Heuvel L 《Pediatric nephrology (Berlin, Germany)》2012,27(9):1519-1524
Background
Atypical hemolytic uremic syndrome (aHUS) is associated with mutations affecting complement proteins and regulators and with autoantibodies against complement factor H (CFH). Approximately half of the aHUS patients progress to end-stage renal disease. DNA analysis of the risk factor genes is important for prognosis of aHUS recurrence after renal transplantation.Methods
Mutational screening of C3 encoding the central complement component was performed by Sanger sequencing in 70 aHUS patients. Mutated and wild type recombinant C3b proteins were produced and their affinity to CFH was analyzed by ELISA.Results
A single novel missense change p.Lys65Gln in C3 was found in 3 aHUS patients. The alteration leads to decreased binding of C3b to CFH in vitro. All three patients acquired the illness as adults and had a first aHUS episode after renal transplantation or suffered recurrence of the disease after transplantation.Conclusions
The novel C3 change was found in 3 aHUS patients. It results in decreased C3b binding to CFH and thus might lead to impaired C3b inactivation in vivo. The p.Lys65Gln is likely to be associated with aHUS after kidney transplantation and, therefore, might be an important prognostic factor. 相似文献2.
Ha Tran Abanti Chaudhuri Waldo Concepcion Paul C. Grimm 《Pediatric nephrology (Berlin, Germany)》2014,29(3):477-480
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. 相似文献3.
4.
Damien Noone Aoife Waters Fred G. Pluthero Denis F. Geary Michael Kirschfink Peter F. Zipfel Christoph Licht 《Pediatric nephrology (Berlin, Germany)》2014,29(5):841-851
Background
Deficiency of complement factor H-related (CFHR) proteins and CFH autoantibody-positive hemolytic uremic syndrome (DEAP-HUS) represents a unique subgroup of complement-mediated atypical HUS (aHUS). Autoantibodies to the C-terminus of CFH block CFH surface recognition and mimic mutations found in the genetic form of (CFH-mediated) aHUS. CFH autoantibodies are found in 10–15 % of aHUS patients and occur—so far unexplained—almost exclusively in the background of CFHR1 or CFHR3/CFHR1 deletions.Methods
As a well-defined role for eculizumab in the treatment of complement-mediated aHUS is becoming established, its role in DEAP-HUS is less conspicuous, where a B-cell-depleting and immunosuppressive treatment strategy is being proposed in the literature.Results
We here show eculizumab to be safe and effective in maintaining a disease-free state, without recurrence, in a previously plasma-therapy-dependent DEAP-HUS patient, and in another patient in whom, although showing a good clinical response to plasma therapy, the therapy was hampered by allergic reactions to fresh frozen plasma and contend there is a rationale for the use of eculizumab in concert with an immunosuppressive strategy in the treatment of DEAP-HUS. Considering the high rate of early relapse, the possible coexistence and contribution of both known and unknown complement-gene mutations, the probable pathogenic role of CFHR1 as a complement alternative pathway (CAP) regulator, the experimental nature of measuring and using anti-CFH autoantibodies to guide management, and until the positive reports of immunosuppression in addition to plasma therapy are confirmed in prospective studies, we feel that a complement-directed therapy should not be neglected in DEAP-HUS. Serial CFH autoantibody titer testing may become a valuable tool to monitor treatment response, and weaning patients off eculizumab may become an option once CFH autoantibody levels are depleted.Conclusions
A prospective study of eculizumab treatment in a larger cohort of DEAP-HUS patients is required to validate the applicability of our positive experience. 相似文献5.
Stephen J. Eyler Nicole C. Meyer Yuzhou Zhang Xue Xiao Carla M. Nester Richard J. H. Smith 《Pediatric nephrology (Berlin, Germany)》2013,28(11):2221-2225
Background
Mutations in complement factor H (CFH) are associated with complement dysregulation and the development of an aggressive form of atypical hemolytic uremic syndrome (aHUS) that progresses to end-stage renal disease (ESRD) and in most patients has a high rate of recurrence following transplantation. Sequence analysis of CFH and its downstream complement factor H-related genes (CFHR1-5) reveals several macrohomologous blocks caused by large genomic duplications. This high degree of sequence identity renders this area susceptible to nonallelic homologous recombination (NAHR) events, resulting in large-scale deletions, duplications, and the generation of hybrid CFH genes.Case-Diagnosis
Here, we report the finding of a novel CFHR1/CFH hybrid gene created by a de novo NAHR event in a 14-year-old girl with aHUS. The resulting fusion protein contains the first three short consensus repeats (SCRs) of CFHR1 and the terminal two SCRs of CFH.Conclusions
This finding demonstrates a novel pathogenic mechanism for the development of aHUS. Additionally, since standard Sanger sequencing is unable to detect such rearrangements, all aHUS patients should receive comprehensive genetic screening that includes analysis of copy number variation in order to identify patients with poor clinical prognoses. 相似文献6.
Karolis Ažukaitis Chantal Loirat Michal Malina Irina Adomaitienė Augustina Jankauskienė 《Pediatric nephrology (Berlin, Germany)》2014,29(7):1273-1277
Background
Atypical hemolytic uremic syndrome (aHUS) is a disorder of the complement system which leads to thrombotic microangiopathy. It is caused by either acquired or hereditary defects in the activation or regulation of the alternative complement pathway and is therefore considered to be a disease of local complement dysregulation in microvasculature with predominantly renal involvement. However, extrarenal manifestations are observed in approximately one-fifth of aHUS patients, with the myocardium and central nervous system (CNS) being involved most often. Additionally, there have been a few reports of aHUS with cerebral artery stenoses or periphereal gangrene, suggesting the possibility of ‘macrovascular’ involvement in aHUS.Case-diagnosis/treatment
We present a child with early onset aHUS and a C3 gain-of-function mutation who developed cerebral artery stenoses, leading ultimately to death due to a massive stroke 9 days after successful renal transplantation under prophylactic eculizumab treatment. Similar cases described in the literature are also briefly summarized.Conclusions
The disease course in our patient with aHUS confirms that dysregulated complement activation can induce arterial steno-occlusive lesions in the absence of acute episodes of HUS. Further studies are required to document the frequency of such macrovascular complications and the role of eculizumab treatment in preventing their development and progression. 相似文献7.
Elena Román-Ortiz Santiago Mendizabal Oteiza Sheila Pinto Margarita López-Trascasa Pilar Sánchez-Corral Santiago Rodríguez de Cordoba 《Pediatric nephrology (Berlin, Germany)》2014,29(1):149-153
Background
Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) caused by dysregulation of the complement system. Outcomes of kidney transplantation are poor owing to aHUS recurrence and loss of graft. Patients carrying CFH mutations or CFH/CFHR1 hybrid genes present a very high risk of recurrence despite preventive plasmapheresis. Evaluation of recent data suggests that prophylactic eculizumab pretransplant might be the preferred therapy if available.Case-diagnosis/treatment
We report 3-year follow-up data in a 9-year-old boy with aHUS and successful renal transplant treated with prophylactic eculizumab without recurrence. He presented with aHUS at age 3, irreversible renal failure and uncontrolled severe hypertension with concentric left ventricular hypertrophy, recurrent acute pulmonary edema, and congestive heart failure despite five hypotensive agents and bilateral nephrectomy. Complement analysis demonstrated the presence of a CFH/CFHR1 hybrid gene inherited from his mother and a SNP risk CFH haplotype inherited from his father. Kidney transplant was performed with prophylactic eculizumab and subsequent fortnightly administration. Three years post-transplant, graft function remains stable (serum creatinine 0.9 mg/dl), hypertension is controlled, no left ventricular hypertrophy, no opportunistic infections, and negative clinical chemistry parameters for hemolysis.Conclusion
Eculizumab is a safe and effective therapy for preventing TMA recurrence and provides long-term graft function in aHUS with the CFH/CFHR1 hybrid gene. 相似文献8.
F. Semsa Caycı Nilgun Cakar Veysel Sabri Hancer Nermin Uncu Banu Acar Gokce Gur 《Pediatric nephrology (Berlin, Germany)》2012,27(12):2327-2331
Background
Hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in childhood. It usually occurs after a prodromal episode of diarrhea and it leads to significant morbidity and mortality during the acute phase. However, cases that start as diarrhea-positive HUS whose renal function fail to recover should be screened for genetic disorders of the complement system, which is called atypical HUS (aHUS).Case-Diagnosis/Treatment
We herein report a 10-year-old girl, who initially came with bloody diarrhea and had features of HUS with delayed renal and hematological recovery despite plasma therapy. Eculizumab (600 mg/week) was initiated on day 15 for atypical presentation and later a complement factor I (CFI) mutation was detected. The girl recovered diuresis within 24 h and after the third eculizumab infusion, hemoglobin, platelet, and C3 levels normalized; renal function improved; and proteinuria completely disappeared in 2 weeks.Conclusion
It is our belief that eculizumab can be the treatment of choice in children who have plasma exchange-refractory HUS with defective regulation of the alternative complement pathway. 相似文献9.
Hefziba Green Emanuel Harari Miriam Davidovits Dorit Blickstein Alon Grossman Uzi Gafter 《Renal failure》2014,36(7):1119-1121
Background: Anti-complement factor H (CFH) antibodies is an extremely rare cause of atypical hemolytic uremic syndrome (aHUS) in adults, with less than 10 cases reported thus far. Although infectious diarrhea is a common inciting trigger for aHUS episode, there are no reports of an association with inflammatory bowel disease. Eculizumab is an emerging treatment for aHUS. Eculizumab has not been reported thus far to be given for aHUS due to anti-CFH antibodies. We report here for the first time on an adult patient with ulcerative colitis (UC) who developed aHUS due to anti-CFH antibodies, presented with decreased serum levels of both C3 and C4. She had an excellent response to treatment with eculizumab. Case presentation: A 27-year-old Caucasian woman, who suffered from steroid-dependent UC, was admitted with microangiopathic hemolytic anemia and acute kidney injury with nephrotic syndrome. ADAMTS 13 was normal and comprehensive workout for secondary causes of HUS was negative. Both serum complement level of C3 and C4 were low. Kidney biopsy was compatible with the diagnosis of HUS with negative immunofluorescence. Because of only partial response to plasma exchange and high dose steroids, eculizumab was commenced. After two weeks signs of microangiopathy subsided, and kidney function began to recover. Few months after the diagnosis, a complement components investigation revealed antibodies against CFH at high titer of 2000 arbitrary units. Today her creatinine is stable with no proteinuria and no signs of HUS. 相似文献
10.
Gwenaëlle Sana Marie-Agnès Dragon-Durey Marina Charbit Karim Bouchireb Caroline Rousset-Rouvière Etienne Bérard Rémi Salomon Véronique Frémeaux-Bacchi Patrick Niaudet Olivia Boyer 《Pediatric nephrology (Berlin, Germany)》2014,29(1):75-83
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. 相似文献11.
Nesrin Besbas Bora Gulhan Diana Karpman Rezan Topaloglu Ali Duzova Emine Korkmaz Fatih Ozaltin 《Pediatric nephrology (Berlin, Germany)》2013,28(1):155-158
Background
Atypical hemolytic uremic syndrome (aHUS) is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Neonatal cases are extremely uncommon. Plasma therapy is the first choice therapy in patients with aHUS based on the belief of an underlying complement dysregulation. Alternatively, eculizumab, which targets complement 5, is used to block complement activation.Case-diagnosis/treatment
Sudden onset macroscopic hematuria, hypertension, and bruises over the entire body were noted in a 5 day-old newborn. Investigations revealed hemolytic anemia, thrombocytopenia, renal impairment, and a low serum C3, leading to the diagnosis of aHUS. Fresh frozen plasma (FFP) infusions and peritoneal dialysis for acute kidney injury were initiated. This approach yielded full renal and hematological remission. The patient was discharged with FFP infusions, but subsequently developed three life-threatening disease recurrences at 1, 3, and 6 months of age. The last relapse presented with uncontrolled hypertension and impaired renal function while the patient was receiving FFP infusions. After the first dose of eculizumab, his renal and hematological parameters returned to normal and his blood pressure normalized. Genetic screening of the CFH gene revealed a novel homozygous p. Tyr1177Cys mutation.Conclusion
Eculizumab can be considered as an alternative to plasma therapy in the treatment of specific patients with aHUS, even in infants. 相似文献12.
Astrid Godron Sabine Pereyre Catherine Monet Brigitte Llanas Jérôme Harambat 《Pediatric nephrology (Berlin, Germany)》2013,28(10):2057-2060
Background
Mycoplasma pneumoniae can cause various extrapulmonary manifestations but, to our knowledge, no case of Mycoplasma pneumoniae associated with hemolytic uremic syndrome (HUS) has been reported.Case-Diagnosis/Treatment
We describe a 1-year-old boy with M. pneumoniae respiratory tract infection and associated microangiopathic hemolytic anemia, slightly decreased platelet count and mild renal impairment, suggesting a diagnosis of HUS. Assuming M. pneumoniae infection was the cause of HUS in this case, the different possible mechanisms, including an atypical HUS due to preexisting complement dysregulation, an alternative complement pathway activation induced by M. pneumoniae infection at the acute phase, an autoimmune disorder, and a direct role of the bacteria in inducing endothelial injury, are discussed. The signs of HUS resolved with treatment of the M. pneumoniae infection.Conclusions
Hemolytic uremic syndrome may be an unusual complication of M. pneumoniae infection. 相似文献13.
Rosanna Coppo Roberto Bonaudo R. Licia Peruzzi Alessandro Amore Andrea Brunati Renato Romagnoli Mauro Salizzoni Miriam Galbusera Eliana Gotti Erica Daina Marina Noris Giuseppe Remuzzi 《Pediatric nephrology (Berlin, Germany)》2016,31(5):759-768
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.14.
Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome 总被引:4,自引:0,他引:4
Sellier-Leclerc AL Fremeaux-Bacchi V Dragon-Durey MA Macher MA Niaudet P Guest G Boudailliez B Bouissou F Deschenes G Gie S Tsimaratos M Fischbach M Morin D Nivet H Alberti C Loirat C;French Society of Pediatric Nephrology 《Journal of the American Society of Nephrology : JASN》2007,18(8):2392-2400
Mutations in factor H (CFH), factor I (IF), and membrane cofactor protein (MCP) genes have been described as risk factors for atypical hemolytic uremic syndrome (aHUS). This study analyzed the impact of complement mutations on the outcome of 46 children with aHUS. A total of 52% of patients had mutations in one or two of known susceptibility factors (22, 13, and 15% of patients with CFH, IF, or MCP mutations, respectively; 2% with CFH+IF mutations). Age <3 mo at onset seems to be characteristic of CFH and IF mutation-associated aHUS. The most severe prognosis was in the CFH mutation group, 60% of whom reached ESRD or died within <1 yr. Only 30% of CFH mutations were localized in SCR20. MCP mutation-associated HUS has a relapsing course, but none of the children reached ESRD at 1 yr. Half of patients with IF mutation had a rapid evolution to ESRD, and half recovered. Plasmatherapy seemed to have a beneficial effect in one third of patients from all groups except for the MCP mutation group. Only eight (33%) of 24 kidney transplantations that were performed in 15 patients were successful. Graft failures were due to early graft thrombosis (50%) or HUS recurrence. In conclusion, outcome of HUS in patients with CFH mutation is catastrophic, and posttransplantation outcome is poor in all groups except for the MCP mutation group. New therapies are urgently needed, and further research should elucidate the unexplained HUS group. 相似文献
15.
Geerdink LM Westra D van Wijk JA Dorresteijn EM Lilien MR Davin JC Kömhoff M Van Hoeck K van der Vlugt A van den Heuvel LP van de Kar NC 《Pediatric nephrology (Berlin, Germany)》2012,27(8):1283-1291
Background
Mutations in complement factor H (CFH), factor I (CFI), factor B (CFB), thrombomodulin (THBD), C3 and membrane cofactor protein (MCP), and autoantibodies against factor H (αFH) with or without a homozygous deletion in CFH-related protein 1 and 3 (?CFHR1/3) predispose development of atypical hemolytic uremic syndrome (aHUS).Methods
Different mutations in genes encoding complement proteins in 45 pediatric aHUS patients were retrospectively linked with clinical features, treatment, and outcome.Results
In 47% of the study participants, potentially pathogenic genetic anomalies were found (5xCFH, 4xMCP, and 4xC3, 3xCFI, 2xCFB, 6xαFH, of which five had ?CFHR1/3); four patients carried combined genetic defects or a mutation, together with αFH. In the majority (87%), disease onset was preceeded by a triggering event; in 25% of cases diarrhea was the presenting symptom. More than 50% had normal serum C3 levels at presentation. Relapses were seen in half of the patients, and there was renal graft failure in all except one case following transplant.Conclusions
Performing adequate DNA analysis is essential for treatment and positive outcome in children with aHUS. The impact of intensive initial therapy and renal replacement therapy, as well as the high risk of recurrence of aHUS in renal transplant, warrants further understanding of the pathogenesis, which will lead to better treatment options. 相似文献16.
Ramon Vilalta Enrique Lara Alvaro Madrid Sara Chocron Marina Muñoz Alex Casquero Jose Nieto 《Pediatric nephrology (Berlin, Germany)》2012,27(12):2323-2326
Background
Atypical hemolytic uremic syndrome (aHUS) is a rare genetic disorder caused by chronic uncontrolled complement activation.Case-diagnosis/treatment
We present a 4-year-old girl with aHUS who had multiple severe clinical manifestations of thrombotic microangiopathy (TMA) including acute kidney injury, dilated cardiomyopathy, and cardiorespiratory arrest. She was managed with intensive plasma exchange and hemodialysis, which could not halt the progression of TMA. The initial single dose of eculizumab only temporarily improved the clinical symptoms of TMA. Sustained improvement of renal, hematological, and cardiac values were only achieved upon institution of chronic treatment with eculizumab. During long-term treatment with eculizumab (>2.5 years), she has had no further clinical manifestations of TMA, and required neither plasma exchange nor hemodialysis.Conclusion
Chronic eculizumab treatment was associated with control of complement-mediated TMA and sustained long-term improvement in renal and cardiac function. 相似文献17.
Kaan Gulleroglu Kibriya Fidan Veysel S. Hançer Umut Bayrakci Esra Baskin Oguz Soylemezoglu 《Pediatric nephrology (Berlin, Germany)》2013,28(5):827-830
Background
Atypical hemolytic uremic syndrome (aHUS) is associated with defective regulation of the complement pathway. Neurological involvement is the most common extrarenal complication and represents a major cause of mortality and morbidity.Case-diagnosis/treatment
Two girls aged 11 and 6 years, respectively, developed aHUS and were treated immediately with plasma exchange (PE) and fresh frozen plasma infusion (PI). Although initial improvement in renal function was seen in both cases, the first patient showed progressing thrombotic microangiopathy (TMA) despite daily PE, and neurological manifestations (seizures, vision loss, loss of balance, and confusion) developed after 1 month. The second patient developed cerebral TMA (seizures, vision loss, and nystagmus) 6 days after initial presentation and remained unresponsive to PE/PI. Neurological symptoms were similar in both patients, even though they had different complement protein mutations. Treatment with eculizumab achieved complete control of neurological symptoms within 24 h and gradually normalized hematological and renal parameters in both children.Conclusions
Based on our two cases, we conclude that eculizumab is a rapid-acting, effective, and life-saving treatment for pediatric patients with aHUS and severe neurological involvement, which works by inhibiting complement-mediated TMA in the kidney and other organs, such as the brain. 相似文献18.
P. Dedhia A. Govil G. Mogilishetty R.R. Alloway E.S. Woodle B.G. Abu Jawdeh 《Transplantation proceedings》2017,49(1):188-192
Background
Atypical hemolytic uremic syndrome (aHUS) is associated with significant morbidity and mortality and occurs due to genetic or acquired abnormalities that result in the dysregulation of the alternative complement pathway.Case Report
We report a case of post-living kidney transplantation de novo aHUS in a setting of heterozygous deletion in the complement factor H-related protein (CFHR)3-CFHR1 gene. The aHUS episode was possibly triggered by antibody-mediated rejection or tacrolimus. The patient responded well to eculizumab and substituting belatacept for tacrolimus. Her serum creatinine level was stable at 1.5 mg/dL after 2.5 years of follow-up.Conclusion
This case highlights the success of using a strategy that combines eculizumab and belatacept, as an alternative to calcineurin inhibitors, in treating aHUS in a patient with heterozygous deletion in the CFHR3-CFHR1 gene. 相似文献19.
de Jorge EG Macor P Paixão-Cavalcante D Rose KL Tedesco F Cook HT Botto M Pickering MC 《Journal of the American Society of Nephrology : JASN》2011,22(1):137-145
Gene variants in the alternative pathway of the complement system strongly associate with atypical hemolytic uremic syndrome (aHUS), presumably by predisposing to increased complement activation within the kidney. Complement factor H (CFH) is the major regulator of complement activation through the alternative pathway. Factor H-deficient mice transgenically expressing a mutant CFH protein (Cfh(-/-).FHΔ16-20) that functionally mimics the CFH mutations reported in aHUS patients spontaneously develop thrombotic microangiopathy. To investigate the role of complement C5 activation in this aHUS model, we generated C5-deficient Cfh(-/-).FHΔ16-20 mice. Both C5-sufficient and C5-deficient Cfh(-/-).FHΔ16-20 mice had abnormal C3 deposition within the kidney, but spontaneous aHUS did not develop in any of the C5-deficient mice. Furthermore, although Cfh(-/-).FHΔ16-20 animals demonstrated marked hypersensitivity to experimentally triggered renal injury, animals with concomitant C5 deficiency did not. These data demonstrate a critical role for C5 activation in both spontaneous aHUS and experimentally triggered renal injury in animals with defective complement factor H function. This study provides a rationale to investigate therapeutic inhibition of C5 in human aHUS. 相似文献
20.
Sally Johnson Jelena Stojanovic Gema Ariceta Martin Bitzan Nesrin Besbas Michelle Frieling Diana Karpman Daniel Landau Craig Langman Christoph Licht Carmine Pecoraro Magdalena Riedl Ekaterini Siomou Nicole van de Kar Johan Vande Walle Chantal Loirat C. Mark Taylor 《Pediatric nephrology (Berlin, Germany)》2014,29(10):1967-1978