Late pregnancy complications as a triggers of obstetric atypical hemolytic uremic syndrome

Obstetric atypical hemolytic-uremic syndrome (aHUS) is considered as a classic complement-mediated TMA, the trigger of which is pregnancy itself. However, there is reason to believe that in women who do not have a genetic defect in the complement system, the induction of acute thrombotic microangiopathy (TMA) requires the presence of additional complement-activating states (CAS) that may complicate pregnancy. The aim of our study was to assess the effect of pregnancy complications on the development, course, and prognosis of obstetric ASH in a large group of patients Methods: 69 patients aged 16 to 44 years with aHUS diagnosed were observed from 2011 to 2019, which developed during pregnancy or immediately after childbirth. Results: in all cases, additional CAS preceded the development of aHUS. The amount of CAS did not significantly differ between patients with pathogenic mutations of complement genes and without them and did not affect the severity of the course of aHUS. The most common combination of CAS was preeclampsia - cesarean section - bleeding. 40 out of 69 patients (58%) received treatment with the complement-blocking drug Eculizumab. Almost a half of them (19 out of 40, 47.5%) received only 1 to 5 infusions. Among 40 patients treated with Eculizumab, complete recovery of renal function was observed in 26 (65%) women, four (10%) retained signs of CKD 4-5 stages, five (12.5%) reached terminal renal failure and 5 patients (12.5%) died. Among 29 women who received only plasma therapy, renal function restoration was noted only in10 (34.5%). An analysis of the development conditions and features of the aHUS course indicates a heterogeneity of the obstetric aHUS. The latter can develop both in genetically predisposed women and in patients without a genetic defect in the complement system. In the latter case, complement activity apparently arises as a result of the interaction of several CAS. This explains the effectiveness of the short-term course of Eculizumab.

тромботическая микроангиопатия, беременность, акушерский атипичный гемолитико-уремический синдром, экулизумаб, thrombotic microangiopathy, pregnancy, obstetric atypical hemolytic-uremic syndrome, eculizumab

1. Loirat C., Frémeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet. J. Rare Dis. 2011; Sep 8;6:60. doi: 10.1186/1750-1172-6-60.

2. Hossain MA, Cheema A, Kalathil S et al. Atypical hemolytic uremic syndrome: laboratory characteristics, complement-amplifying conditions, renal biopsy, and genetic mutations. Saudi J. Kidney Dis.Transpl. 2018 Mar-Apr; 29(2):276-283. doi: 10.4103/1319-2442.229287.

3. Коротчаева Ю.В., Козловская Н.Л., Демьянова К.А., и др. Генетические аспекты акушерского атипичного гемолитико-уремического синдрома. Клиническая нефрология. 2017; №1: 12-17

4. Kozlovskaya N.L., Korotchaeva Y.V., Bobrova L.A. Adverse outcomes in obstetric-atypical haemolyticuraemic syndrome: a case series analysis. J. Matern. Fetal. Neonat. al. Med. 2018; Apr 1:1-7. doi: 10.1080/14767058.2018.1450381

5. Zhang T., Lu J., Liang S., Chen D. et al. Comprehensive Analysis of Complement Genes in Patients with Atypical Hemolytic Uremic Syndrome. Am. J. Nephrol. 2016; 43(3):160-9. doi: 10.1159/000445127

6. Fakhouri F., Roumenina L., Provot F. et al. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J.Am.Soc.Nephrol. 2010; 21:859-867.

7. Fakhouri F., Vercel C., Frémeaux-Bacchi V. Obstetric nephrology: AKI and thrombotic microangiopathies in pregnancy. Clin.J.Am.Soc.Nephrol. 2012 Dec; 7(12):2100-6. doi: 10.2215/CJN.13121211.

8. Gaggl M., Aigner C., Csuka D et al. Maternal and Fetal Outcomes of Pregnancies in Women with Atypical Hemolytic Uremic Syndrome. J. Am. Soc. Nephrol. 2018 Mar; 29(3):1020-1029. doi: 10.1681/ASN.2016090995

9. Bruel A., Kavanagh D., Noris M. et.al. Hemolytic uremic syndrome in pregnancy and post-partum. Clin. J. Am. Soc.Nephrol. 2017;12: doi:https//doi.org/10.2215/CJN.00280117

10. Fujisawa M., Kato H., Yoshida Y. et al. Correction to: Clinical characteristics and genetic backgrounds of Japanese patients with atypical hemolytic uremic syndrome. Clin. Exp. Nephrol. 2019 Jul;23(7):985. doi: 10.1007/s10157-019-01728-3.

11. Huerta A., Arjona E., Portoles J. et al. A retrospective study of pregnancy-associated atypical hemolytic uremic syndrome. Kidney Int. 2018 Feb;93(2):450-459. doi: 10.1016/j.kint.2017.06.022.

12. Fan X., Yoshida Y., Honda S. et al. Analysis of genetic and predisposing factors in Japanese patients with atypical hemolytic uremic syndrome. MolImmunol2013; 54: 238-246

13. Боброва Л.А., Козловская Н.Л., Шкарупо В.В. и соавт. Влияние генетической формы тромбофилии на клинико-морфологические проявления и характер течения хронического гломерулонефрита. Нефрология и диализ. 2010; Т. 12. № 1. С. 25-33.

14. Козловская Н.Л., Коротчаева Ю.В., Шифман Е.М., Боброва Л.А. Атипичный гемолитико-уремический синдром как одна из причин острого повреждения почек у беременных Терапевтический архив. 2018; Т. 90. № 6. С. 28-34.

15. Козловская Н.Л., Коротчаева Ю.В., Боброва Л.А., Шилов Е.М. Акушерский атипичный гемолитико-уремический синдром: первый российский опыт диагностики и лечения. Нефрология. 2016;20(2):68-80.

16. Кирсанова Т.В., Виноградова М.А., Шмаков Р.Г. Развитие атипичного гемоаитико-уремического синдрома после гинекологической операции: особенности клинической картины, диагностики и лечения Акушерство и гинекология. 2018; № 1. С. 154-160. DOI: 10.18565/aig.2018.1.154-160

17. Tingi E., Sabir N., Verghese L. Postpartum atypical haemolyticuraemic syndrome in a pre-eclamptic patient. Int. J. Reprod.Contracept.Obstet.Gynecol. 2016;5(3):894-898 doi: 10.18203/2320-1770.ijrcog20160607

18. Козловская Н.Л., Меркушева Л.И., Кирсанова Т.В. и соавт. Влияние дисбаланса плацентарных факторов ангиогенеза на клинические проявления "ранней" и "своевременной" преэклампсии. Нефрология и диализ. 2013; Т. 15. № 3. С. 206-215.

19. Меркушева Л.И., Козловская Н.Л. Поражение почек при преэклампсии: взгляд нефролога (обзор литературы). Нефрология. 2018; 22(2):30-38. https://doi.org/10.24884/1561-6274-2018-22-2-30-38

20. Tsai H.M. A Mechanistic Approach to the Diagnosis and Management of Atypical Hemolytic Uremic Syndrome.Transfus. Med.Rev. 2014; Oct;28(4):187-197.

21. Т.В. Кирсанова, М.А. Виноградова, А.И. Колыванова. Обособленность Hellp-синдрома от преэклампсии: особенности поражения почек и других органов, Клиническая Нефрология. 2018, №4:66-73. doi: https://dx.doi.org/10.18565/Nephrology.2018.4.33-41

22. Riedl M., Fakhouri F., Le Quintrec M. et al. Spectrum of complement-mediated thrombotic microangiopathies: Pathogenetic insights identifying novel treatment approaches. Semin.Thromb. Hemost. 2014;40:444-64. doi: 10.1055/s-0034-1376153.

23. Le Clech A., Simon-Tillaux N., Provôt F. et al. Atypical and secondary hemolytic uremic syndromes have a distinct presentation and no common genetic risk factors. Kidney Int. 2019 Jun; 95(6):1443-1452. doi: 10.1016/j.kint.2019.01.023.

24. Praga M., de Cordoba SR. Secondary atypical hemolytic uremic syndromes in the era of complement blockade. Kidney International 2019;95:1298-1300 doi: 10.1016/j.kint.2019.01.043.

25. Noris M., Mescia F., Remuzzi G. STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat. Rev. Nephrol. 2012 Nov; 8(11):622-33. doi: 10.1038/nrneph.2012.195.

26. Nürnberger J., Philipp T., Witzke O. Et al. Eculizumab for atypical hemolytic-uremic syndrome. N.Engl.J. Med. 2009; Jan 29;360(5):542-4. doi: 10.1056/NEJMc0808527

27. CaveroT., Rabasco C., López A. et al. Eculizumab in secondary atypical haemolytic uraemic syndrome. Nephrol Dial Transplant. 2017 Mar 1; 32(3):466-474. doi: 10.1093/ndt/gfw453

28. Menne J., Delmas Y., Fakhouri F. et al. Outcomes in patients with atypical hemolytic uremic syndrome treated with eculizumab in a long-term observational study. BMC Nephrol. 2019 Apr 10;20(1):125. doi: 10.1186/s12882-019-1314-1.