Различные фенотипы акушерского атипичного гемолитико-уремического синдрома: роль генетического обследования для определения прогноза

Кирсанова Т.В., Балакирева А.И., Федорова Т.А., Пырегов А.В., Рогачевский О.В. Различные фенотипы акушерского атипичного гемолитико-уремического синдрома: роль генетического обследования для определения прогноза. Терапевтический архив. 2023;95(6):511–515.
DOI: 10.26442/00403660.2023.06.202233

© ООО «КОНСИЛИУМ МЕДИКУМ», 2023 г.

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Kirsanova TV, Balakireva AI, Fedorova TA, Pyregov AV, Rogachevskiy OV. Various phenotypes of postpartum atypical hemolytic uremic syndrome: the role of genetic testing in determining prognosis. Case report. Terapevticheskii Arkhiv (Ter. Arkh.). 2023;95(6):511–515. DOI: 10.26442/00403660.2023.06.202233

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Аннотация

Описан случай диагностики и лечения атипичного гемолитико-уремического синдрома (аГУС) – крайне редкого заболевания, характеризующегося развитием тромботической микроангиопатии (ТМА) с преимущественным острым повреждением почек, у пациентки, имеющей в анамнезе многочисленные рецидивирующие эпизоды ТМА с нефротической протеинурией и нарушением функции почек. В 33 нед первой самопроизвольной беременности впервые зарегистрирована протеинурия до 0,8 г/л, в 38 нед госпитализирована с протеинурией, максимально достигающей 13 г/л, родоразрешена оперативно, после чего в течение последующих нескольких дней отмечена прогрессирующая тромбоцитопения (до 44×109/л) и анемия. Обращала на себя внимание не поддающаяся коррекции сразу несколькими группами антигипертензивных препаратов артериальная гипертензия и явления острого повреждения почек с азотемией до 266 мкмоль/л. Инициированная плазмотерапия не оказала эффекта. После исключения всех иных причин ТМА инициирована терапия экулизумабом, позволившая быстро и полно купировать явления ТМА. Представленное наблюдение демонстрирует успешное лечение рецидивирующего течения аГУС экулизумабом с достижением полного восстановления функции почек у пациентки с гомозиготной мутацией в гене МСР. Стоит отметить важность генетического исследования даже в тех ситуациях, когда клинически аГУС не вызывает сомнений.

Ключевые слова: атипичный гемолитико-уремический синдром, диацилглицеринокиназа эпсилон, мембранный кофакторный протеин, генетическое исследование белков – регуляторов комплемента, антикомплементарная терапия, экулизумаб

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We report a case of atypical hemolytic uremic syndrome (aHUS) that occurred after childbirth in a patient with a history of numerous recurrent episodes of TMA with nephrotic proteinuria and impaired renal function. At 33 weeks of the first spontaneous pregnancy, proteinuria up to 0.8 g/l was first registered, at 38 weeks she was hospitalized with proteinuria, reaching a maximum of 13 g/l, she was delivered promptly, after which progressive thrombocytopenia was noted over the next few days (up to 44×109/l) and anemia and severe arterial hypertension, which could not be corrected by several groups of antihypertensive drugs. Initiated plasma therapy had no effect. After exclusion of all other causes of TMA, therapy with eculizumab was initiated, which made it possible to quickly and completely stop the phenomena of TMA. The presented observation demonstrates the successful treatment of recurrent course of aHUS with eculizumab with the achievement of complete recovery of kidney function in a patient with a homozygous mutation in the MCP gene. It is worth noting the importance of genetic research even in those situations where clinically aHUS is beyond doubt.

Keywords: atypical hemolytic uremic syndrome, diacylglycerinokinase epsilon, membrane cofactor protein, genetic study of complement regulator proteins, eculizumab

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Список литературы

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DOI:10.32756/0869-5490-2021-3-25-30

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1. Moake JL. Thrombotic microangiopathies. N Engl J Med. 2002;347(8):589-600. DOI:10.1056/NEJMra020528
2. de Cordoba SR, Tortajada A, Harris CL, Morgan BP. Complement dysregulation and disease: from genes and proteins to diagnostics and drugs. Immunobiology. 2012;217(11):1034-46. DOI:10.1016/j.imbio.2012.07.021
3. Noris M, Brioschi S, Caprioli J, et al. Familial haemolytic uraemic syndrome and an MCP mutation. Lancet. 2003;362(9395):1542-7. DOI:10.1016/S0140-6736(03)14742-3
4. Pérez-Caballero D, González-Rubio C, Gallardo ME, et al. Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome. Am J Hum Genet. 2001;68(2):478-84. DOI:10.1086/318201
5. Richards A, Kemp EJ, Liszewski MK, et al. Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proc Natl Acad Sci USA. 2003;100(22):12966-71. DOI:10.1073/pnas.2135497100
6. Warwicker P, Goodship TH, Donne RL, et al. Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int. 1998;53(4):836-44.
DOI:10.1111/j.1523-1755.1998.00824.x
7. Esparza-Gordillo J, Goicoechea de Jorge E, Buil A, et al. Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32. Hum Mol Genet. 2005;14(5):703-12. DOI:10.1093/hmg/ddi066
8. Fremeaux-Bacchi V, Dragon-Durey MA, Blouin J, et al. Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J Med Genet. 2004;41(6):e84. DOI:10.1136/jmg.2004.019083
9. Frémeaux-Bacchi V, Miller EC, Liszewski MK, et al. Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood. 2008;112(13):4948-52. DOI:10.1182/blood-2008-01-133702
10. Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J, et al. Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc Natl Acad Sci USA. 2007;104(1):240‑5. DOI:10.1073/pnas.0603420103
11. Feitz WJ, van de Kar NC, Orth-Höller D, et al. The genetics of atypical hemolytic uremic syndrome. Med Genet. 2018;30(4):400-9. DOI:10.1007/s11825-018-0216-0
12. Quaggin SE. DGKE and atypical HUS. Nat Genet. 2013;45(5):475-6. DOI:10.1038/ng.2622
13. de Córdoba SR. Complement genetics and susceptibility to inflammatory disease. Lessons from genotype-phenotype correlations. Immunobiology. 2016;221(6):709-14. DOI:10.1016/j.imbio.2015.05.015
14. Nester CM, Barbour T, de Cordoba SR, et al. Atypical aHUS: State of the art. Mol Immunol. 2015;67(1):31-42. DOI:10.1016/j.molimm.2015.03.246
15. Kearney HM, Thorland EC, Brown KK, et al. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 2011;13(7):680-5. DOI:10.1097/GIM.0b013e3182217a3a
16. Kaplan BS, Meyers KE, Schulman SL. The pathogenesis and treatment of hemolytic uremic syndrome. J Am Soc Nephrol. 1998;9(6):1126-33. DOI:10.1681/ASN.V961126
17. Noris M, Remuzzi G. Hemolytic uremic syndrome. J Am Soc Nephrol. 2005;16(4):1035-50. DOI:10.1681/ASN.2004100861
18. Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, et al. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2007;18(8):2392-400. DOI:10.1681/ASN.2006080811
19. Constantinescu AR, Bitzan M, Weiss LS, et al. Non-enteropathic hemolytic uremic syndrome: causes and short-term course. Am J Kidney Dis. 2004;43(6):976-82. DOI:10.1053/j.ajkd.2004.02.010
20. Ariceta G, Besbas N, Johnson S, et al. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol. 2009;24(4):687-96. DOI:10.1007/s00467-008-0964-1
21. Noris M, Caprioli J, Bresin E, et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol. 2010;5(10):1844-59. DOI:10.2215/CJN.02210310
22. Davin JC, Buter N, Groothoff J, et al. Prophylactic plasma exchange in CD46-associated atypical haemolytic uremic syndrome. Pediatr Nephrol. 2009;24(9):1757-60. DOI:10.1007/s00467-009-1188-8
23. Matsukuma E, Gotoh Y, Kuroyanagi Y, et al. A case of atypical hemolytic uremic syndrome due to anti-factor H antibody in a patient presenting with a factor XII deficiency identified two novel mutations. Clin Exp Nephrol. 2011;15(2):269-74. DOI:10.1007/s10157-010-0375-z
24. Kirsanova TV, Kozlovskaya NL, Kalashnikova LA, et al. Renal affection in a patient with Sneddon's syndrome. Terapevticheskii Arkhiv (Ter. Arkh.). 2009;81(8):73-7 (in Russian).
25. Shilov EM, Kozlovskaya NL, Meteleva NA, et al. Clinical manifestations of nephropathy associated with antiphospholipid syndrome in primary antiphosphoflipid syndrome. Terapevticheskii Arkhiv (Ter. Arkh.). 2003;75(6):22-8 (in Russian).
26. Makanjuola AD, Scoble JE. Ischaemic nephropathy – is the diagnosis excluded by heavy proteinuria? Nephrol Dial Transplant. 1999;14(12):2795-7. DOI:10.1093/ndt/14.12.2795
27. Huerta A, Arjona E, Portoles J, et al. A retrospective study of pregnancy-associated atypical hemolytic uremic syndrome. Kidney Int. 2018;93(2):450-9. DOI:10.1016/j.kint.2017.06.022
28. Kulagin A, Ptushkin V, Lukina E, et al. Randomized multicenter noninferiority phase III clinical trial of the first biosimilar of eculizumab. Ann Hematol. 2021;100(11):2689-98. DOI:10.1007/s00277-021-04624-7
29. Kulagin A, Ptushkin V, Lukina E, et al. Phase III clinical trial of Elizaria® and Soliris® in adult patients with paroxysmal nocturnal hemoglobinuria: results of comparative analysis of efficacy, safety, and pharmacological data. Blood. 2019;134(Suppl. 1):3748. DOI:10.1182/blood-2019-125693
30. Ptushkin VV, Kulagin AD, Lukina EA, et al. Results of phase Ib open multicenter clinical trial of the safety, pharmacokinetics and pharmacodynamics of first biosimilar of eculizumab in untreated patients with paroxysmal nocturnal hemoglobinuria during induction of therapy. Terapevticheskii Arkhiv (Ter. Arkh.). 2020;92(7):77-84 (in Russian). DOI:10.26442/00403660.2020.07.000818
31. Korotchaeva YV, Kozlovskaya N., Shifman EM. Comparative efficacy of the original and biosimilar eculizumab in the treatment of obstetric atypical hemolytic-uremic syndrome. Clinical Pharmacology and Therapy. 2021;30(3):25-30 (in Russian). DOI:10.32756/0869-5490-2021-3-25-30

Авторы

Т.В. Кирсанова*1, А.И. Балакирева2, Т.А. Федорова1, А.В. Пырегов1, О.В. Рогачевский1

1 ФГБУ «Национальный медицинский исследовательский центр акушерства, гинекологии и перинатологии им. акад. В.И. Кулакова» Минздрава России, Москва, Россия;
2 ФГБОУ ВО «Московский государственный университет им. М.В. Ломоносова», Москва, Россия
*a_tatya@mail.ru

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Tatiana V. Kirsanova*1, Alina I. Balakireva2, Tatiana A. Fedorova1, Aleksei V. Pyregov1, Oleg V. Rogachevskiy1

1 Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia;
2 Lomonosov Moscow State University, Moscow, Russia
*a_tatya@mail.ru

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