Skip to main content

Advertisement

SpringerLink
Log in

Systematic review of atypical hemolytic uremic syndrome biomarkers

  • Systematic Review/Meta-analysis
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Background and objectives

Observing biomarkers that affect alternative pathway dysregulation components may be effective in obtaining a new and more rapid diagnostic portrayal of atypical hemolytic uremic syndrome. We have conducted a systematic review on the aHUS biomarkers: C3, C5a, C5b-9, factor B, complement factor B, H, and I, CH50, AH50, d-dimer, as well as anti-CFH antibodies.

Methods

An exhaustive literature search was conducted for aHUS patient population plasma/serum, collected/reported at the onset of diagnosis. A total of 60 studies were included with the data on 837 aHUS subjects, with at least one biomarker reported.

Results

The biomarkers C3 [mean (SD): 72.1 (35.0), median: 70.5 vs. reference range: 75–175 mg/dl, n = 752]; CH50 [28.3 (32.1), 24.3 vs. 30–75 U/ml, n = 63]; AH50 [27.6% (30.2%), 10% vs. ≥ 46%, n = 23]; and CFB [13.1 (6.6), 12.4, vs. 15.2–42.3 mg/dl, n = 19] were lower among aHUS subjects as compared with the reference range.

The biomarkers including C4 [mean (SD): 20.4 (9.5), median: 20.5 vs. reference range: 14–40 mg/dl, n = 343]; C4d [7.2 (6.5), 4.8 vs. ≤ 9.8 μg/ml, n = 108]; CFH [40.2 (132.3), 24.5 vs. 23.6–43.1 mg/dl, n = 123 subjects]; and CFI [8.05 (5.01), 6.55 mg/dl vs. 4.4–18.1 mg/dl, n = 38] were all observed to be within the reference range among aHUS subjects.

The biomarkers C5a [mean (SD): 54.9 (32.9), median: 48.8 vs. reference range: 10.6–26.3 mg/dl, n = 117]; C5b-9 [466.0 (401.4), 317 (186–569.7) vs. ≤ 250 ng/ml, n = 174]; Bb [2.6 (2.1), 1.9 vs. ≤ 1.6 μg/ml, n = 77] and d-dimer [246 (65.05), 246 vs. < 2.2 ng/ml, 2, n = 2 subjects] were higher among patients with aHUS compared with the reference range.

Conclusion

If a comprehensive complement profile were built using our data, aHUS would be identified by low levels of C3, CH50, AH50, and CFB along with increased levels of C5a, C5b-9, Bb, anti-CFH autoantibodies, and d-dimer.

Graphical abstract

A higher resolution version of the Graphical abstract is available as Supplementary information.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

Code availability

Microsoft Word. SPSS version 22.

Abbreviations

aHUS :

Atypical hemolytic uremic syndrome

AP:

Alternative pathway

TMA:

Thrombotic microangiopathy

TTP:

Thrombotic thrombocytopenic purpura

STEC-HUS:

Shiga toxin-producing Escherichia coli hemolytic uremic syndrome

CFB:

Complement factor B

CFH:

Complement factor H

CFI:

Complement factor I

MAC:

Membrane attack complex

TCC:

Terminal complement complex

References

  1. Noris M, Caprioli J, Bresin E, Mossali C et al (2010) Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 5:1844–1859. https://doi.org/10.2215/CJN.02210310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Yoshida Y, Kato H, Ikeda Y, Nangaku M (2019) Pathogenesis of atypical hemolytic uremic syndrome. J Atheroscler Thromb 26:99–110. https://doi.org/10.5551/jat.RV17026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Moake JL (2002) Thrombotic Microangiopathies. N Engl J Med 347:589–600. https://doi.org/10.1056/NEJMra020528

    Article  CAS  PubMed  Google Scholar 

  4. Oh J, Oh D, Lee SJ, Kim JO, Korean TTP Registry Investigators et al (2019) Prognostic utility of ADAMTS13 activity for the atypical hemolytic uremic syndrome (aHUS) and comparison of complement serology between aHUS and thrombotic thrombocytopenic purpura. Blood Res 54:218–228. https://doi.org/10.5045/br.2019.54.3.218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kato H, Nangaku M, Hataya H, Sawai T et al (2016) Clinical guides for atypical hemolytic uremic syndrome in Japan. Clin Exp Nephrol 20:536–543. https://doi.org/10.1007/s10157-016-1276-6

    Article  CAS  PubMed  Google Scholar 

  6. Cataland SR, Holers VM, Geyer S, Yang S, Wu HM (2014) Biomarkers of terminal complement activation confirm the diagnosis of aHUS and differentiate aHUS from TTP. Blood 123:3733–3738. https://doi.org/10.1182/blood-2013-12-547067

    Article  CAS  PubMed  Google Scholar 

  7. Nguyen MH, Mathew JJ, Denunzio TM, Carmichael MG (2014) Diagnosis of atypical hemolytic uremic syndrome and response to eculizumab therapy. Hawaii J Med Public Health 73(9 Suppl 1):22–24

    PubMed  PubMed Central  Google Scholar 

  8. Avila Bernabeu AI, Cavero Escribano T, Cao Vilarino M (2020) Atypical hemolytic uremic syndrome: new challenges in the complement blockage era. Nephron 144:537–549. https://doi.org/10.1159/000508920

    Article  CAS  PubMed  Google Scholar 

  9. Cofiell R, Kukreja A, Bedard K, Yan Y et al (2015) Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS. Blood 125:3253–3262. https://doi.org/10.1182/blood-2014-09-600411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Richards A, Kathryn Liszewski M, Kavanagh D, Fang CJ, Moulton E, Fremeaux-Bacchi V, Remuzzi G, Noris M, Goodship TH, Atkinson JP (2007) Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome. Mol Immunol 44:111–122. https://doi.org/10.1016/j.molimm.2006.07.004

    Article  CAS  PubMed  Google Scholar 

  11. Puraswani M, Khandelwal P, Saini H, Saini S et al (2019) Clinical and immunological profile of anti-factor H antibody associated atypical hemolytic uremic syndrome: a nationwide database. Front Immunol 10:1282. https://doi.org/10.3389/fimmu.2019.01282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Noris M, Remuzzi G (2013) Managing and preventing atypical hemolytic uremic syndrome recurrence after kidney transplantation. Curr Opin Nephrol Hypertens 22:704–712. https://doi.org/10.1097/MNH.0b013e328365b3fe

    Article  CAS  PubMed  Google Scholar 

  14. Esparza-Gordillo J, Goicoechea de Jorge E, Buil A, Carreras Berges L et al (2005) Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32 [published correction appears in Hum Mol Genet 14:1107]. Hum Mol Genet 14:703–712. https://doi.org/10.1093/hmg/ddi066

    Article  CAS  PubMed  Google Scholar 

  15. Bresin E, Rurali E, Caprioli J, Sanchez-Corral P et al (2013) Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype. J Am Soc Nephrol 24:475–486. https://doi.org/10.1681/ASN.2012090884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lemaire M, Frémeaux-Bacchi V, Schaefer F, Choi M et al (2013) Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet 45:531–536. https://doi.org/10.1038/ng.2590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, Macher MA et al (2007) Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol 18:2392–2400. https://doi.org/10.1681/ASN.2006080811

    Article  CAS  PubMed  Google Scholar 

  18. Hofer J, Janecke AR, Zimmerhackl LB, Riedl M et al (2013) Complement factor H-related protein 1 deficiency and factor H antibodies in pediatric patients with atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol 8:407–415. https://doi.org/10.2215/CJN.01260212

    Article  CAS  PubMed  Google Scholar 

  19. Valoti E, Alberti M, Iatropoulos P, Piras R et al (2019) Rare functional variants in complement genes and anti-FH autoantibodies-associated aHUS. Front Immunol 10:853. https://doi.org/10.3389/fimmu.2019.00853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dragon-Durey MA (2005) Anti-factor h autoantibodies associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol 16:555–563. https://doi.org/10.1681/asn.2004050380

    Article  CAS  PubMed  Google Scholar 

  21. Lee JM, Park YS, Lee JH, Park SJ et al (2015) Atypical hemolytic uremic syndrome: Korean pediatric series. Pediatr Int 57:431–438. https://doi.org/10.1111/ped.12549

    Article  PubMed  Google Scholar 

  22. Bernabéu-Herrero ME, Jiménez-Alcázar M, Anter J, Pinto S et al (2015) Complement factor H, FHR-3 and FHR-1 variants associate in an extended haplotype conferring increased risk of atypical hemolytic uremic syndrome. Mol Immunol 67:276–286. https://doi.org/10.1016/j.molimm.2015.06.021

    Article  CAS  PubMed  Google Scholar 

  23. Dragon-Durey MA, Blanc C, Marliot F, Loirat C et al (2009) The high frequency of complement factor H related CFHR1 gene deletion is restricted to specific subgroups of patients with atypical haemolytic uraemic syndrome. J Med Genet 46:447–450. https://doi.org/10.1136/jmg.2008.064766

    Article  CAS  PubMed  Google Scholar 

  24. Leban N, Aloui S, Touati D, Lakhdhar R et al (2011) Atypical hemolytic uremic syndrome in the Tunisian population. Int Urol Nephrol 43:559–564. https://doi.org/10.1007/s11255-010-9754-3

    Article  PubMed  Google Scholar 

  25. Józsi M, Licht C, Strobel S, Zipfel SL et al (2008) Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency. Blood 111:1512–1514. https://doi.org/10.1182/blood-2007-09-109876

    Article  CAS  PubMed  Google Scholar 

  26. Moore I, Strain L, Pappworth I, Kavanagh D et al (2010) Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome. Blood 115:379–387. https://doi.org/10.1182/blood-2009-05-221549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Matsumoto T, Toyoda H, Amano K, Hirayama M et al (2018) Clinical manifestation of patients with atypical hemolytic uremic syndrome with the C3 p.I1157T variation in the Kinki Region of Japan. Clin Appl Thromb Hemost 24:1301–1307. https://doi.org/10.1177/1076029618771750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Martínez-Barricarte R, Heurich M, López-Perrote A, Perrote-Lopez A, Tortajada A et al (2015) The molecular and structural bases for the association of complement C3 mutations with atypical hemolytic uremic syndrome. Mol Immunol 66:263–273. https://doi.org/10.1016/j.molimm.2015.03.248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fan X, Yoshida Y, Honda S, Matsumoto M, Sawada Y et al (2013) Analysis of genetic and predisposing factors in Japanese patients with atypical hemolytic uremic syndrome. Mol Immunol 54:238–246. https://doi.org/10.1016/j.molimm.2012.12.006

    Article  CAS  PubMed  Google Scholar 

  30. Manenti L, Gnappi E, Vaglio A, Allegri L et al (2013) Atypical haemolytic uraemic syndrome with underlying glomerulopathies. A case series and a review of the literature. Nephrol Dial Transplant 28:2246–2259. https://doi.org/10.1093/ndt/gft220

    Article  CAS  PubMed  Google Scholar 

  31. Malina M, Gulati A, Bagga A, Majid MA, Simkova E, Schaefer F (2013) Peripheral gangrene in children with atypical hemolytic uremic syndrome. Pediatrics 131:e331–e335. https://doi.org/10.1542/peds.2012-0903

    Article  PubMed  Google Scholar 

  32. Roumenina LT, Jablonski M, Hue C, Blouin J et al (2009) Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome. Blood 114:2837–2845. https://doi.org/10.1182/blood-2009-01-197640

    Article  CAS  PubMed  Google Scholar 

  33. Lee BH, Kwak SH, Shin JI, Lee SH et al (2009) Atypical hemolytic uremic syndrome associated with complement factor H autoantibodies and CFHR1/CFHR3 deficiency. Pediatr Res 66:336–340. https://doi.org/10.1203/PDR.0b013e3181b1bd4a

    Article  CAS  PubMed  Google Scholar 

  34. Galbusera M, Noris M, Gastoldi S, Bresin E et al (2019) An ex vivo test of complement activation on endothelium for individualized eculizumab therapy in hemolytic uremic syndrome. Am J Kidney Dis 74:56–72. https://doi.org/10.1053/j.ajkd.2018.11.012

    Article  CAS  PubMed  Google Scholar 

  35. Volokhina EB, Westra D, van der Velden TJ, van de Kar NC, Mollnes TE, van den Heuvel LP (2015) Complement activation patterns in atypical haemolytic uraemic syndrome during acute phase and in remission. Clin Exp Immunol 181:306–313. https://doi.org/10.1111/cei.12426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mortensen S, Kidmose RT, Petersen SV, Szilágyi Á, Prohászka Z, Andersen GR (2015) Structural basis for the function of complement component C4 within the classical and lectin pathways of complement. J Immunol 194:5488–5496. https://doi.org/10.4049/jimmunol.1500087

    Article  CAS  PubMed  Google Scholar 

  37. Sridharan M, Go RS, Abraham RS, Fervenza FC, Sethi S, Bryant SC, Spears GM, Murray DL, Willrich MAV (2018) Diagnostic utility of complement serology for atypical hemolytic uremic syndrome. Mayo Clin Proc 93:1351–1362. https://doi.org/10.1016/j.mayocp.2018.07.008

    Article  PubMed  Google Scholar 

  38. Noris M, Galbusera M, Gastoldi S, Macor P et al (2014) Dynamics of complement activation in aHUS and how to monitor eculizumab therapy. Blood 124:1715–1726. https://doi.org/10.1182/blood-2014-02-558296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Al Ustwani O, Lohr J, Dy G, LeVea C et al (2014) Eculizumab therapy for gemcitabine induced hemolytic uremic syndrome: case series and concise review. J Gastrointest Oncol 5:E30–E33

    PubMed  PubMed Central  Google Scholar 

  40. Okusawa S, Yancey KB, van der Meer JW, Endres S et al (1988) C5a stimulates secretion of tumor necrosis factor from human mononuclear cells in vitro. Comparison with secretion of interleukin 1 beta and interleukin 1 alpha. J Exp Med 168:443–448. https://doi.org/10.1084/jem.168.1.443

    Article  CAS  PubMed  Google Scholar 

  41. Prohászka Z, Varga L, Füst G (2012) The use of ‘real-time’ complement analysis to differentiate atypical haemolytic uraemic syndrome from other forms of thrombotic microangiopathies. Br J Haematol 158:424–425

    Article  Google Scholar 

  42. Tsai HM, Kuo E (2014) Eculizumab therapy leads to rapid resolution of thrombocytopenia in atypical hemolytic uremic syndrome. Adv Hematol 2014:295323

    Article  Google Scholar 

  43. Charles Jennette JJ, Hussein Gasim AM Pathology of medical renal disease. In: Reisner HM (ed) Pathology: A Modern Case Study, 2e. McGraw-Hill

  44. Jaskowski TD, Martins TB, Litwin CM, Hill HR (1999) Comparison of three different methods for measuring classical pathway complement activity. Clin Diagn Lab Immunol 6:137–139. https://doi.org/10.1128/CDLI.6.1.137-139.1999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Schröder-Braunstein J, Kirschfink M (2019) Complement deficiencies and dysregulation: Pathophysiological consequences, modern analysis, and clinical management. Mol Immunol 114:299–311

    Article  Google Scholar 

  46. Kolb WP, Morrow PR, Tamerius JD (1989) Ba and Bb fragments of factor B activation: fragment production, biological activities, neoepitope expression and quantitation in clinical samples. Complement Inflamm 6:175–204

    Article  CAS  Google Scholar 

  47. Willrich MAV, Andreguetto BD, Sridharan M, Fervenza FC et al (2018) The impact of eculizumab on routine complement assays. J Immunol Methods 460:63–71. https://doi.org/10.1016/j.jim.2018.06.010

    Article  CAS  PubMed  Google Scholar 

  48. Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J, Carreras L et al (2007) Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome [published correction appears in Proc Natl Acad Sci U S A 104:10749]. Proc Natl Acad Sci U S A 104:240–245. https://doi.org/10.1073/pnas.0603420103

    Article  CAS  PubMed  Google Scholar 

  49. Wong E, Kavanagh D (2018) Diseases of complement dysregulation-an overview. Semin Immunopathol 40:49–64. https://doi.org/10.1007/s00281-017-0663-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Nilsson SC, Sim RB, Lea SM, Fremeaux-Bacchi V, Blom AM (2011) Complement factor I in health and disease. Mol Immunol 48:1611–1620

    Article  CAS  Google Scholar 

  51. Bu F, Maga T, Meyer NC, Wang K et al (2014) Comprehensive genetic analysis of complement and coagulation genes in atypical hemolytic uremic syndrome. J Am Soc Nephrol 25:55–64. https://doi.org/10.1681/ASN.2013050453

    Article  CAS  PubMed  Google Scholar 

  52. Lee BC, Mayer CL, Leibowitz CS, Stearns-Kurosawa DJ, Kurosawa S (2013) Quiescent complement in nonhuman primates during E coli Shiga toxin-induced hemolytic uremic syndrome and thrombotic microangiopathy. Blood 122:803–806. https://doi.org/10.1182/blood-2013-03-490060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Palma LM, Langman CB (2016) Critical appraisal of eculizumab for atypical hemolytic uremic syndrome. J Blood Med 7:39–72. https://doi.org/10.2147/JBM.S36249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Knight EL, Verhave JC, Spiegelman D, Hillege HL, de Zeeuw D, Curhan GC, de Jong PE (2004) Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int 65:1416–1421. https://doi.org/10.1111/j.1523-1755.2004.00517.x

    Article  CAS  PubMed  Google Scholar 

  55. Randers E, Kristensen JH, Erlandsen EJ, Danielsen H (1998) Serum cystatin C as a marker of the renal function. Scand J Clin Lab Invest 58:585–592. https://doi.org/10.1080/00365519850186210

    Article  CAS  PubMed  Google Scholar 

  56. Ghiggeri GM, Bruschi M, Candiano G, Rastaldi MP et al (2002) Depletion of clusterin in renal diseases causing nephrotic syndrome. Kidney Int 62:2184–2194

    Article  CAS  Google Scholar 

  57. Fraga-Rodriguez GM, Brió-Sanagustin S, Turón-Viñas E, Dixon BP, Carreras-González E (2017) Eculizumab in a child with atypical haemolytic uraemic syndrome and haemophagocytic lymphohistiocytosis triggered by cytomegalovirus infection. BMJ Case Rep 2017:bcr2016219065

    Article  Google Scholar 

  58. Zheng X, Chen S, Zhang F, Ye M, Chen J, Zhang S (2021) Use of fibrin monomer and D-Dimer in assessing overt and nonovert disseminated intravascular coagulation. Blood Coagul Fibrinolysis 32:248–252. https://doi.org/10.1097/MBC.0000000000001025

    Article  CAS  PubMed  Google Scholar 

  59. Loirat C, Fakhouri F, Ariceta G, Besbas N et al (2016) An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol 31:15–39. https://doi.org/10.1007/s00467-015-3076-8

    Article  PubMed  Google Scholar 

  60. Noris M, Bresin E, Mele C, Remuzzi G (2007) Genetic atypical hemolytic-uremic syndrome. In: Adam MP, Ardinger HH, Pagon RA et al (eds) GeneReviews®. University of Washington, Seattle, Seattle

    Google Scholar 

  61. Dragon-Durey MA, Sethi SK, Bagga A, Blanc C et al (2010) Clinical features of anti-factor H autoantibody-associated hemolytic uremic syndrome. J Am Soc Nephrol 21:2180–2187. https://doi.org/10.1681/ASN.2010030315

    Article  PubMed  PubMed Central  Google Scholar 

  62. Ermini L, Goodship TH, Strain L, Weale ME et al (2012) Common genetic variants in complement genes other than CFH, CD46 and the CFHRs are not associated with aHUS. Mol Immunol 49:640–648. https://doi.org/10.1016/j.molimm.2011.11.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kavanagh D, Pappworth IY, Anderson H, Hayes CM et al (2012) Factor I autoantibodies in patients with atypical hemolytic uremic syndrome: disease-associated or an epiphenomenon? Clin J Am Soc Nephrol 7:417–426. https://doi.org/10.2215/CJN.05750611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Govindarajan S, Rawat A, Ramachandran R, Hans R, Dawman L, Tiewsoh K (2020) Anti-complement factor I antibody associated atypical hemolytic uremic syndrome—a new insight for future perspective! Immunobiology 225:152000. https://doi.org/10.1016/j.imbio.2020.152000

    Article  CAS  PubMed  Google Scholar 

  65. Fremeaux-Bacchi V, Dragon-Durey MA, Blouin J, Vigneau C et al (2004) Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J Med Genet 41:e84. https://doi.org/10.1136/jmg.2004.019083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Johnson S, Stojanovic J, Ariceta G, Bitzan M et al (2014) An audit analysis of a guideline for the investigation and initial therapy of diarrhea negative (atypical) hemolytic uremic syndrome. Pediatr Nephrol 29:1967–1978. https://doi.org/10.1007/s00467-014-2817-4

    Article  PubMed  Google Scholar 

  67. Fakhouri F, Hourmant M, Campistol JM, Cataland SR, Espinosa M, Gaber AO, Menne J, Minetti EE, Provôt F, Rondeau E, Ruggenenti P, Weekers LE, Ogawa M, Bedrosian CL, Legendre CM (2016) Terminal complement inhibitor eculizumab in adult patients with atypical hemolytic uremic syndrome: a single-arm, open-label trial. Am J Kidney Dis 68:84–93

    Article  CAS  Google Scholar 

  68. Legendre C, Rebecca-Sberro-Soussan ZJ (2021) Ravulizumab for the treatment of aHUS in adults: improving quality of life. Kidney Int Rep 6:1489–1491. https://doi.org/10.1016/j.ekir.2021.04.036

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  70. Legendre CM, Licht C, Muus P, Greenbaum LA et al (2013) Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 368:2169–2181. https://doi.org/10.1056/NEJMoa1208981

    Article  CAS  PubMed  Google Scholar 

  71. McKeage K (2019) Ravulizumab: first global approval. Drugs 79:347–352. https://doi.org/10.1007/s40265-019-01068-2

    Article  CAS  PubMed  Google Scholar 

  72. Tanaka K, Adams B, Aris AM, Fujita N et al (2021) The long-acting C5 inhibitor, ravulizumab, is efficacious and safe in pediatric patients with atypical hemolytic uremic syndrome previously treated with eculizumab [published correction appears in Pediatr Nephrol 36:1033]. Pediatr Nephrol 36:889–898. https://doi.org/10.1007/s00467-020-04774-2

    Article  PubMed  Google Scholar 

  73. Gäckler A, Schönermarck U, Dobronravov V, La Manna G et al (2021) Efficacy and safety of the long-acting C5 inhibitor ravulizumab in patients with atypical hemolytic uremic syndrome triggered by pregnancy: a subgroup analysis [published correction appears in BMC Nephrol 22:49]. BMC Nephrol 22:5. https://doi.org/10.1186/s12882-020-02190-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Rondeau E, Scully M, Ariceta G, Barbour T et al (2020) The long-acting C5 inhibitor, Ravulizumab, is effective and safe in adult patients with atypical hemolytic uremic syndrome naïve to complement inhibitor treatment [published correction appears in Kidney Int 98:1621] [published correction appears in Kidney Int 99:1244]. Kidney Int 97:1287–1296. https://doi.org/10.1016/j.kint.2020.01.035

    Article  CAS  PubMed  Google Scholar 

  75. Tesar V, Hruskova Z (2018) Avacopan in the treatment of ANCA-associated vasculitis. Expert Opin Investig Drugs 27:491–496. https://doi.org/10.1080/13543784.2018.1472234

    Article  CAS  PubMed  Google Scholar 

  76. Turkmen K, Baloglu I, Ozer H (2021) C3 glomerulopathy and atypical hemolytic uremic syndrome: an updated review of the literature on alternative complement pathway disorders. Int Urol Nephrol 53:2067–2080. https://doi.org/10.1007/s11255-020-02729-y

    Article  PubMed  Google Scholar 

  77. US Food and Drug Administration (2015) Scientific considerations in demonstrating biosimilarity to a reference product. Guidance for industry. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Silver Spring

  78. Ptushkin VV, Kulagin AD, Lukina EA, Davydkin IL, Konstantinova TS, Shamrai VS, Minaeva NV, Kudlay DA, Gapchenko EV, Markova OA, Borozinets AY (2020) 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. Ter Arkh 92:77–84. https://doi.org/10.26442/00403660.2020.07.000818

    Article  CAS  PubMed  Google Scholar 

  79. Hutterer K, Polozova A, Kuhns S et al (2019) Analytical and functional similarity of proposed Amgen biosimilar ABP 959 to eculizumab. Presented at 2019 PDA Biosimilars and Vaccines Conference: Lifecycle Similarities and Challenges, Long Beach, CA; May 9-10

  80. Chow V, Pan J, Chien D, Mytych DT, Hanes V (2020) A randomized, double-blind, single-dose, three-arm, parallel group study to determine pharmacokinetic similarity of ABP 959 and eculizumab (Soliris® ) in healthy male subjects. Eur J Haematol 105:66–74. https://doi.org/10.1111/ejh.13411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Samsung Bioepis Co., Ltd (2019) A study to compare SB12 (proposed Eculizumab biosimilar) to Soliris in subjects with paroxysmal nocturnal haemoglobinuria—full text view. ClinicalTrials.gov

Download references

Funding

The authors have received no financial support for the creation of this manuscript and have no disclosures to report.

Author information

Authors and Affiliations

  1. Akron Nephrology Associates/Cleveland Clinic Akron General Medical Center, Akron, OH, USA

    Rupesh Raina & Amrit Khooblall

  2. Department of Nephrology, Akron Children’s Hospital, Akron, OH, USA

    Rupesh Raina & Amrit Khooblall

  3. Kidney and Renal Transplant Institute, Medanta, The Medicity Hospital, Gurgaon, Haryana, India

    Sidharth K. Sethi

  4. Hôpital Européen Georges Pompidou, APHP, INSERM UMRS1138, Université de Paris, Paris, France

    Marie-Agnès Dragon-Durey

  5. Department of Medicine, Northeast Ohio Medical University, Rootstown, OH, USA

    Divya Sharma

  6. Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India

    Priyanka Khandelwal & Arvind Bagga

  7. The Mount Sinai Hospital, New York, NY, USA

    Ron Shapiro

  8. Service de Néphrologie Pédiatrique, AP-HP, Centre de Référence de maladies rénales rares de l’enfant et de l’adulte (MARHEA), Hôpital Necker - Enfants Malades, 149 Rue de Sèvres, 75015, Paris, France

    Olivia Boyer

  9. Institut Imagine, Laboratoire des maladies rénales héréditaires, INSERM UMR 1163, Université de Paris, Paris, France

    Olivia Boyer

  10. Shaw-NKF-NUH Children’s Kidney Centre, Khoo Teck Puat-National University Children’s Medical Institute, National University Hospital, Kent Ridge, Singapore

    Hui Kim Yap

  11. Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Hui Kim Yap

  12. Cell Biology Program, SickKids Research Institute, Toronto, ON, Canada

    Christoph Licht

  13. Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Christoph Licht

  14. Division of Nephrology, The Hospital for Sick Children, Toronto, ON, Canada

    Christoph Licht

Authors
  1. Rupesh Raina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sidharth K. Sethi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marie-Agnès Dragon-Durey
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amrit Khooblall
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Divya Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Priyanka Khandelwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ron Shapiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Olivia Boyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hui Kim Yap
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Arvind Bagga
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Christoph Licht
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Dr. Raina was the lead author who formulated, structured and wrote this manuscript. Dr. Sethi, Dr. Dragon-Durey, Dr. Shaprio, Dr. Boyer, Dr. Yap, Dr. Bagga, and Dr. Licht all lent their expertise in this field to continuously revise all drafts for their accuracy steering the content to potential clinical applicability. Amrit Khooblall. Divya Sharma, and Priyanka Khandelwal all extensively reviewed, corrected, and edited this manuscript.

Corresponding author

Correspondence to Rupesh Raina.

Ethics declarations

Ethics approval

An ethics statement is not applicable because this study is based exclusively on published literature.

Consent for publication

All authors consent for publication.

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PPTX 538 kb)

Supplementary file2 (DOCX 188 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Raina, R., Sethi, S.K., Dragon-Durey, MA. et al. Systematic review of atypical hemolytic uremic syndrome biomarkers. Pediatr Nephrol 37, 1479–1493 (2022). https://doi.org/10.1007/s00467-022-05451-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-022-05451-2

Keywords

Search

Navigation