Exploratory Prognostic Biomarkers of Complement-Mediated Thrombotic Microangiopathy (CM-TMA) in Adults with Atypical Hemolytic Uremic Syndrome (aHUS): Analysis of a Phase III Study of Ravulizumab
Tobin J Cammett, Katherine Garlo, Ellen E Millman, Kara Rice, Catherine M Toste, Susan J Faas, Tobin J Cammett, Katherine Garlo, Ellen E Millman, Kara Rice, Catherine M Toste, Susan J Faas
Abstract
Background: Clinically validated biomarkers for monitoring of patients with complement-mediated thrombotic microangiopathy (CM-TMA) including atypical hemolytic uremic syndrome (aHUS) are unavailable. Improved characterization of biomarkers in patients with aHUS may inform treatment and monitoring for patients with CM-TMA.
Methods: This analysis used data collected from 55/56 (98.2 %) adult patients with aHUS enrolled in the global Phase III study of ravulizumab (NCT02949128). Baseline (pre-treatment) patient serum, plasma and urine biomarker levels were compared with the maximum observed levels in normal donors and evaluated for associations with pre-treatment plasma exchange/infusion and dialysis status. Biomarkers were also assessed for associations with key clinical measures at baseline and with changes at 26 and 52 weeks from treatment initiation via linear regression analyses.
Results: Complement-specific urine levels (factor Ba and sC5b-9) were elevated in >85 % of patients and are significantly associated with pre-treatment kidney dysfunction. Baseline levels of other evaluated biomarkers were elevated in >70 % of patients with aHUS, except for plasma sC5b-9 and serum sVCAM-1. Lower levels of urine complement markers at baseline are significantly associated with improvements in total urine protein and estimated glomerular filtration rate at 26 and 52 weeks of treatment. Clinical assessment of complement activation by a receiver operating characteristic analysis of Ba and sC5b-9 was more sensitive and specific in urine matrix than plasma.
Conclusion: This analysis identified a set of biomarkers that may show utility in the prognosis of CM-TMA, including their potential for measuring and predicting response to anti-C5 therapy. Further studies are required to enhance patient risk stratification and improve management of these vulnerable patients.
Clinical trials registration: NCT02949128, ClinicalTrials.gov.
Conflict of interest statement
All authors are employees and stockholders of Alexion, AstraZeneca Rare Disease, Boston, MA, USA.
© 2022. The Author(s).
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References
- Arnold DM, Patriquin CJ, Nazy I. Thrombotic microangiopathies: a general approach to diagnosis and management. CMAJ. 2017;189(4):E153–E159. doi: 10.1503/cmaj.160142.
- Gavriilaki E, Anagnostopoulos A, Mastellos DC. Complement in thrombotic microangiopathies: unraveling Ariadne's thread into the labyrinth of complement therapeutics. Front Immunol. 2019;10:337. doi: 10.3389/fimmu.2019.00337.
- Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361(17):1676–1687. doi: 10.1056/NEJMra0902814.
- Raina R, Krishnappa V, Blaha T, Kann T, Hein W, Burke L, et al. Atypical hemolytic-uremic syndrome: an update on pathophysiology, diagnosis, and treatment. Ther Apher Dial. 2019;23(1):4–21. doi: 10.1111/1744-9987.12763.
- Asif A, Nayer A, Haas CS. Atypical hemolytic uremic syndrome in the setting of complement-amplifying conditions: case reports and a review of the evidence for treatment with eculizumab. J Nephrol. 2017;30(3):347–362. doi: 10.1007/s40620-016-0357-7.
- Lemaire M, Noone D, Lapeyraque A-L, Licht C, Frémeaux-Bacchi V. Inherited kidney complement diseases. Clin J Am Soc Nephrol. 2021;16(6):942. doi: 10.2215/CJN.11830720.
- Thurman JM, Nester CM. All things complement. Clin J Am Soc Nephrol CJASN. 2016;11(10):1856–1866. doi: 10.2215/CJN.01710216.
- Frazer-Abel A, Kirschfink M, Prohászka Z. Expanding horizons in complement analysis and quality control. Front Immunol. 2021 doi: 10.3389/fimmu.2021.697313.
- Galbusera M, Noris M, Gastoldi S, Bresin E, Mele C, Breno M, et al. An ex vivo test of complement activation on endothelium for individualized eculizumab therapy in hemolytic uremic syndrome. Am J Kidney Dis. 2019;74(1):56–72. doi: 10.1053/j.ajkd.2018.11.012.
- Palomo M, Blasco M, Molina P, Lozano M, Praga M, Torramade-Moix S, et al. Complement activation and thrombotic microangiopathies. Clin J Am Soc Nephrol CJASN. 2019;14(12):1719–1732. doi: 10.2215/CJN.05830519.
- Gavriilaki E, Yuan X, Ye Z, Ambinder AJ, Shanbhag SP, Streiff MB, et al. Modified Ham test for atypical hemolytic uremic syndrome. Blood. 2015;125(23):3637–3646. doi: 10.1182/blood-2015-02-629683.
- Noris M, Galbusera M, Gastoldi S, Macor P, Banterla F, Bresin E, et al. Dynamics of complement activation in aHUS and how to monitor eculizumab therapy. Blood. 2014;124(11):1715–1726. doi: 10.1182/blood-2014-02-558296.
- Fakhouri F, Frémeaux-Bacchi V. Monitoring complement activation: the new conundrum in thrombotic microangiopathies. Clin J Am Soc Nephrol CJASN. 2019;14(12):1682–1683. doi: 10.2215/CJN.12111019.
- Goodship TH, Cook HT, Fakhouri F, Fervenza FC, Fremeaux-Bacchi V, Kavanagh D, et al. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. Kidney Int. 2017;91(3):539–551. doi: 10.1016/j.kint.2016.10.005.
- Raina R, Sethi SK, Dragon-Durey MA, Khooblall A, Sharma D, Khandelwal P, et al. Systematic review of atypical hemolytic uremic syndrome biomarkers. Pediatr Nephrol. 2022;37(7):1479–1493. doi: 10.1007/s00467-022-05451-2.
- Blasco M, Guillén E, Quintana LF, Garcia-Herrera A, Piñeiro G, Poch E, et al. Thrombotic microangiopathies assessment: mind the complement. Clin Kidney J. 2020;14(4):1055–1066. doi: 10.1093/ckj/sfaa195.
- Cofiell R, Kukreja A, Bedard K, Yan Y, Mickle AP, Ogawa M, et al. Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS. Blood. 2015;125(21):3253–3262. doi: 10.1182/blood-2014-09-600411.
- Waters AM, Licht C. aHUS caused by complement dysregulation: new therapies on the horizon. Pediatr Nephrol. 2011;26(1):41–57. doi: 10.1007/s00467-010-1556-4.
- Cataland SR, Wu HM. How I treat: the clinical differentiation and initial treatment of adult patients with atypical hemolytic uremic syndrome. Blood. 2014;123(16):2478–2484. doi: 10.1182/blood-2013-11-516237.
- Weitz IC. Complement the hemostatic system: an intimate relationship. Thromb Res. 2014;133(Suppl 2):S117–S121. doi: 10.1016/S0049-3848(14)50020-5.
- Ritis K, Doumas M, Mastellos D, Micheli A, Giaglis S, Magotti P, et al. A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J Immunol. 2006;177(7):4794–4802. doi: 10.4049/jimmunol.177.7.4794.
- Rondeau E, Scully M, Ariceta G, Barbour T, Cataland S, Heyne N, et al. The long-acting C5 inhibitor, ravulizumab, is effective and safe in adult patients with atypical hemolytic uremic syndrome naïve to complement inhibitor treatment. Kidney Int. 2020;97(6):1287–1296. doi: 10.1016/j.kint.2020.01.035.
- Barbour T, Scully M, Ariceta G, Cataland S, Garlo K, Heyne N, et al. Long-term efficacy and safety of the long-acting complement C5 inhibitor ravulizumab for the treatment of atypical hemolytic uremic syndrome in adults. Kidney Int Rep. 2021;6(6):1603–1613. doi: 10.1016/j.ekir.2021.03.884.
- Lee JW, Devanarayan V, Barrett YC, Weiner R, Allinson J, Fountain S, et al. Fit-for-purpose method development and validation for successful biomarker measurement. Pharm Res. 2006;23(2):312–328. doi: 10.1007/s11095-005-9045-3.
- US Food and Drug Administration. Biomarker Qualification: Evidentiary Framework Guidance for Industry and FDA Staff. Draft Guidance. 2018; . Accessed 15 Feb 2022.
- Mazzara S, Rossi RL, Grifantini R, Donizetti S, Abrignani S, Bombaci M. CombiROC: an interactive web tool for selecting accurate marker combinations of omics data. Sci Rep. 2017;7(1):45477. doi: 10.1038/srep45477.
- Protein Microarray and Bioinformatics Facilities INGMReEII, Milan, Italy. CombiROC. 2017; V1.2; last updated 10/02/2017]; V1.2: . Accessed 29 Mar 2022.
- Jodele S, Laskin BL, Dandoy CE, Myers KC, El-Bietar J, Davies SM, et al. A new paradigm: Diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev. 2015;29(3):191–204. doi: 10.1016/j.blre.2014.11.001.
- Bu F, Meyer NC, Zhang Y, Borsa NG, Thomas C, Nester C, et al. Soluble c5b–9 as a biomarker for complement activation in atypical hemolytic uremic syndrome. Am J Kidney Dis. 2015;65(6):968–969. doi: 10.1053/j.ajkd.2015.02.326.
- Volokhina EB, Westra D, van der Velden TJAM, van de Kar NCAJ, Mollnes TE, van den Heuvel LP. Complement activation patterns in atypical haemolytic uraemic syndrome during acute phase and in remission. Clin Exp Immunol. 2015;181(2):306–313. doi: 10.1111/cei.12426.
- Cataland SR, Holers VM, Geyer S, Yang S, Wu HM. Biomarkers of terminal complement activation confirm the diagnosis of aHUS and differentiate aHUS from TTP. Blood. 2014;123(24):3733–3738AS. doi: 10.1182/blood-2013-12-547067.
- Tomazos I, Hatswell AJ, Cataland S, Chen P, Freemantle N, Lommele Å, et al. Comparative efficacy of ravulizumab and eculizumab in the treatment of atypical hemolytic uremic syndrome: An indirect comparison using clinical trial data. Clin Nephrol. 2022;97(5):261–272. doi: 10.5414/CN110516.
Source: PubMed