Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype

被引:754
作者
Noris, Marina [1 ]
Caprioli, Jessica [1 ]
Bresin, Elena [1 ]
Mossali, Chiara [1 ]
Pianetti, Gaia [1 ]
Gamba, Sara [1 ]
Daina, Erica [1 ]
Fenili, Chiara [1 ]
Castelletti, Federica [1 ]
Sorosina, Annalisa [1 ]
Piras, Rossella [1 ]
Donadelli, Roberta [1 ]
Maranta, Ramona [1 ]
van der Meer, Irene [1 ,2 ]
Conway, Edward M. [3 ]
Zipfel, Peter F. [4 ]
Goodship, Timothy H. [5 ]
Remuzzi, Giuseppe [1 ,6 ]
机构
[1] Clin Res Ctr Rare Dis, Mario Negri Inst Pharmacol Res, I-24020 Ranica, BG, Italy
[2] Univ Hosp Maastricht, Div Nephrol, Dept Internal Med, Maastricht, Netherlands
[3] Univ British Columbia, Life Sci Ctr, Ctr Blood Res, Vancouver, BC V5Z 1M9, Canada
[4] Leibniz Inst Nat Prod Res & Infect Biol, Jena, Germany
[5] Newcastle Univ, Inst Human Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England
[6] Osped Riuniti Bergamo, Azienda Osped, Dept Nephrol & Dialysis, I-24100 Bergamo, Italy
来源
CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2010年 / 5卷 / 10期
基金
英国医学研究理事会;
关键词
HEMOLYTIC-UREMIC SYNDROME; LIVER-KIDNEY TRANSPLANT; FACTOR-H-AUTOANTIBODIES; THROMBOTIC MICROANGIOPATHY; RENAL-TRANSPLANTATION; MUTATIONS; ECULIZUMAB;
D O I
10.2215/CJN.02210310
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Background and objectives: Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Most childhood cases are caused by Shiga toxin producing bacteria. The other form, atypical HUS (aHUS), accounts for 10% of cases and has a poor prognosis. Genetic complement abnormalities have been found in aHUS. Design, setting, participants, and measurements: We screened 273 consecutive patients with aHUS for complement abnormalities and studied their role in predicting clinical phenotype and response to treatment. We compared mutation frequencies and localization and clinical outcome in familial (82) and sporadic (191) cases. Results: In >70% of sporadic and familial cases, gene mutations, disease-associated factor H (CFH) polymorphisms, or anti-CFH autoantibodies were found. Either mutations or CFH polymorphisms were also found in the majority of patients with secondary aHUS, suggesting a genetic predisposition. Familial cases showed a higher prevalence of mutations in SCR20 of CFH and more severe disease than sporadic cases. Patients with CFH or THBD (thrombomodulin) mutations had the earliest onset and highest mortality. Membrane-cofactor protein (MCP) mutations were associated with the best prognosis. Plasma therapy induced remission in 55 to 80% of episodes in patients with CFH, C3, or THBD mutations or autoantibodies, whereas patients with CFI (factor I) mutations were poor responders. aHUS recurred frequently after kidney transplantation except for patients with MCP mutations. Conclusions: Results underline the need of genetic screening for all susceptibility factors as part of clinical management of aHUS and for identification of patients who could safely benefit from kidney transplant. Clin J Am Soc Nephrol 5: 1844-1859, 2010. doi: 10.2215/CJN.02210310
引用
收藏
页码:1844 / 1859
页数:16
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