How not to miss atypical hemolytic uremic syndrome in patients on kidney transplant waiting list. Lecture

Atypical hemolytic uremic syndrome (aHUS) is an orphan disease caused by dysregulation and hyperactivation of the alternative complement pathway, which has a characteristic morphological picture of microvascular lesions and a triad (sometimes incomplete) of clinical manifestations: thrombocytopenia, microangiopathic hemolytic anemia, and target organ damage. Excessive activation of complement in aHUS is caused by mutations in genes encoding proteins of the complement system or the formation of antibodies to some of them. The use of complement-blocking therapy with eculizumab has significantly improved the outcomes of patients with aHUS, including the results of kidney transplantation (KT) in patients at high/intermediate risk of recurrent thrombotic microangiopathy (TMA) after transplantation who are treated with eculizumab prophylactically. However, some patients with aHUS, in the absence of the full complex of symptoms, reach CKD G5 and are included in the waiting list for KT without establishing a correct diagnosis, which can have serious consequences: the return of aHUS in the renal graft with a rapid loss of its function, the development of life-threatening manifestations of systemic TMA. Salvage therapy with eculizumab is known to be less effective than its prophylactic administration in patients at risk of relapse after KT. In addition, in the case of aHUS recurrence in the graft, time for patient evaluation is usually limited. The article presents clinical observations demonstrating the difficulty of diagnosing “missed» aHUS in patients on the KT waiting list and after transplantation. When included in the KT waiting list, special vigilance regarding aHUS should be exercised in adolescents and young patients with severe hypertension, treatment-resistant anemia, episodes of thrombocytopenia, any extrarenal lesions, patients who have had typical HUS, women with CKD C5 after severe preeclampsia/HELLP syndrome, as well as in patients who lost their first renal transplant due to TMA. Such patients should undergo a comprehensive examination, including re-evaluation of medical history (including family history), immunological examination to exclude other causes of TMA, genetic testing of the complement system, determination of antibodies to factor H, and kidney biopsy in the absence of a significant reduction in kidney size and high risk of bleeding.

атипичный гемолитико-уремический синдром (аГУС), тромботическая микроангиопатия, трансплантация почки, обследование перед трансплантацией, исходы трансплантации почки, экулизумаб, atypical hemolytic-uremic syndrome (aHUS), thrombotic microangiopathy, kidney transplantation, pretransplant evaluation, postrenal transplant outcomes, eculizumab

1. Thompson G.L., Kavanagh D. Diagnosis and treatment of thrombotic microangiopathy. Int J Lab Hematol. 2022. 44(Suppl 1):101-113. doi: 10.1111/ijlh.13954

2. Brocklebank V., Wood K.M., Kavanagh D. Thrombotic microangiopathy and the kidney. Clin J Am Soc Nephrol. 2018. 13(2):300-317. doi: 10.2215/CJN.00620117

3. Gallan A.J., Chang A. A new paradigm for renal thrombotic microangiopathy. Semin Diagn Pathol. 2020. 37(3):121-126. doi: 10.1053/j.semdp.2020.01.002

4. McFarlane P.A., Bitzan M., Broome C. et al. Making the correct diagnosis in thrombotic microangiopathy: a narrative review. Can J Kidney Health Dis. 2021. 22;8: 20543581211008707. doi: 10.1177/20543581211008707

5. Palma L.M., Vaisbich-Guimarães M.H., Sridharan M. et al. Thrombotic microangiopathy in children. Pediatr Nephrol. 2022. 1-14. doi: 10.1007/s00467-021-05370-8

6. Åkesson A., Martin M., Blom A.M. et al. Clinical characterization and identification of rare genetic variants in atypical hemolytic uremic syndrome: A Swedish retrospective observational study. Ther Apher Dial. 2021. 25(6):988-1000. doi: 10.1111/1744-9987.13634

7. Palma L.M., Sridharan M., Sethi S. Complement in secondary thrombotic microangiopathy. Kidney Int Rep. 2021. 6(1):11-23. DOI: 10.1016/j.ekir.2020.10.009

8. Noris M., Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009. 361(17):1676-1687. doi: 10.1056/NEJMra0902814

9. Le Quintrec M., Zuber J., Moulin B. et al. Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome. Am J Transplant. 2013. 13:663-675. doi: 10.1111/ajt.12077

10. Greenbaum L.A., Fila M., Ardissino G. et al. Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int. 2016. 89(3):701-711. doi: 10.1016/j.kint.2015.11.026

11. Tang Z.C., Hui H., Shi C., Chen X. New findings in preventing recurrence and improving renal function in AHUS patients after renal transplantation treated with eculizumab: a systemic review and meta-analyses. Ren Fail. 2023. 45(1):2231264. doi: 10.1080/0886022X.2023.2231264

12. Hanna R.M., Henriksen K., Kalantar-Zadeh K. et al. Thrombotic microangiopathy syndromes-common ground and distinct frontiers. Adv Chronic Kidney Dis. 2022. 29(2):149-160.e1. doi: 10.1053/j.ackd.2021.11.006

13. Saba E.S., Cambron J.C., Go R.S. et al. Clinical associations, treatment, and outcomes of renal-limited thrombotic microangiopathy. Blood. 2018. 132 (Suppl_1): 4978. doi: 10.1182/blood-2018-99-117723

14. Garlo K., Dressel D., Savic M., Vella J. Successful eculizumab treatment of recurrent postpartum atypical hemolytic uremic syndrome after kidney transplantation. Clin Nephrol Case Stud. 2015. 3:8-13. doi: 10.5414/CNCS108491

15. Ávila A., Vizcaíno B., Molina P. et al. Remission of aHUS neurological damage with eculizumab. Clin Kidney J. 2015. 8(2): 232-236. doi: 10.1093/ckj/sfu144

16. Brocklebank V., Walsh P.R., Smith-Jackson K. et al. Atypical hemolytic uremic syndrome in the era of terminal complement inhibition: an observational cohort study. Blood. 2023. 142(16):1371-1386. doi: 10.1182/blood.2022018833

17. Claes K.J., Massart A., Collard L. et al. Belgian consensus statement on the diagnosis and management of patients with atypical hemolytic uremic syndrome. Acta Clin Belg. 2018. 73(1):80-89. doi: 10.1080/17843286.2017.1345185

18. Tseng M.H., Lin S.H., Tsai J.D. et al. Atypical hemolytic uremic syndrome: Consensus of diagnosis and treatment in Taiwan. J Formos Med Assoc. 2023. 122(5):366-375. doi: 10.1016/j.jfma.2022.10.006

19. Прокопенко Е.И. Применение эверолимуса у de novo реципиентов почечного трансплантата. Вестник трансплантологии и искусственных органов. 2010. 12(2): 74-81.

20. Прокопенко Е.И., Щербакова Е.О., Ватазин А.В. и др. Результаты профилактики цитомегаловирусной инфекции валганцикловиром у пациентов с трансплантированной почкой. Клиническая нефрология. 2013. 5:37-41.

21. Козловская Н.Л., Добронравов В.А., Боброва Л.А. и др. Клинические рекомендации по ведению взрослых пациентов с атипичным гемолитико-уремическим синдромом. Нефрология и диализ. 2023. 25(4):465-492. doi: 10.28996/2618-9801-2023-4-465-492

22. Teixeira C.M., Tedesco Silva Junior H., Moura L.A.R. et al. Clinical and pathological features of thrombotic microangiopathy influencing long-term kidney transplant outcomes. PLoS One. 2020. 15(1):e0227445. doi: 10.1371/journal.pone.0227445

23. Imanifard Z., Liguori L., Remuzzi G. et al. TMA in kidney transplantation. Transplantation. 2023. 107(11):2329-2340. doi: 10.1097/TP.0000000000004585

24. Siedlecki A.M., Isbel N., Vande Walle J. et al. Eculizumab use for kidney transplantation in patients with a diagnosis of atypical hemolytic uremic syndrome. Kidney Int Rep. 2018. 4(3):434-446. doi: 10.1016/j.ekir.2018.11.010

25. Gonzalez Suarez M.L., Thongprayoon C., Mao M.A. et al. Outcomes of kidney transplant patients with atypical hemolytic uremic syndrome treated with eculizumab: a systematic review and meta-analysis. J Clin Med. 2019. 8(7):919. doi: 10.3390/jcm8070919

26. Walle J.V., Delmas Y., Ardissino G. et al. Improved renal recovery in patients with atypical hemolytic uremic syndrome following rapid initiation of eculizumab treatment. J Nephrol. 2017. 30(1):127-134. doi: 10.1007/s40620-016-0288-3

27. Ferraris J.R., Ramirez J.A., Ruiz S. et al. Shiga toxin-associated hemolytic uremic syndrome: absence of recurrence after renal transplantation. Pediatr Nephrol. 2002. 17(10):809-14. doi: 10.1007/s00467-002-0936-9

28. Frémeaux-Bacchi V., Sellier-Leclerc A.L., Vieira-Martins P. et al. Complement gene variants and shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome: retrospective genetic and clinical study. Clin J Am Soc Nephrol. 2019. 14(3):364-377. doi: 10.2215/CJN.05830518

29. Alberti M., Valoti E., Piras R. et al. Two patients with history of STEC-HUS, posttransplant recurrence and complement gene mutations. Am J Transplant. 2013. 13(8):2201-2206. doi: 10.1111/ajt.12297

30. Dowen F., Wood K., Brown A.L. et al. Rare genetic variants in Shiga toxin-associated haemolytic uraemic syndrome: genetic analysis prior to transplantation is essential. Clin Kidney J. 2017. 10(4):490-493. doi: 10.1093/ckj/sfx030

31. Poggio E.D., McClelland R.L., Blank K.N. et al. Systematic review and meta-analysis of native kidney biopsy complications. Clin J Am Soc Nephrol. 2020. 15(11):1595-1602. doi: 10.2215/CJN.04710420

32. Halimi J.-M. Complications after native kidney biopsy: definitive data. Curr Opin Nephrol Hypertens. 2021. 30(6):555-558. doi: 10.1097/MNH.0000000000000736

33. Palma L.M.P., Sridharan M., Sethi S. Complement in secondary thrombotic microangiopathy. Kidney Int Rep. 2021. 6(1):11-23. doi: 10.1016/j.ekir.2020.10.009

34. Miyakis S., Lockshin M.D., Atsumi T. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006. 4(2):295-306. doi: 10.1111/j.1538-7836.2006.01753.x

35. Kim M.J., Lee H., Kim Y.H. et al. Eculizumab therapy on a patient with co-existent lupus nephritis and C3 mutation-related atypical haemolytic uremic syndrome: a case report. BMC Nephrol. 2021. 22(1):86. doi: 10.1186/s12882-021-02293-2

36. Alhamoud I., Freiberg S.A. Successful discontinuation of eculizumab in a pediatric patient with atypical hemolytic uremic syndrome and underlying systematic lupus erythematosus. Cureus. 2022. 14(5):e25117. doi: 10.7759/cureus.25117

37. Manenti L., Rossi G.M., Pisani I. et al. IgA nephropathy and atypical hemolytic uremic syndrome: a case series and a literature review. J Nephrol. 2022. 35(4):1091-1100. doi: 10.1007/s40620-021-01189-6

38. Fremeaux-Bacchi V., Fakhouri F., Garnier A. et al. Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol. 2013. 8(4):554-562. doi: 10.2215/CJN.04760512

39. Blasco M., Guillén E., Quintana L.F. et al. Thrombotic microangiopathies assessment: mind the complement. Clin Kidney J. 2020. 14(4):1055-1066. doi: 10.1093/ckj/sfaa195