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Abstract: FR-PO831

Novel Assays to Distinguish Between Properdin-Dependent and Properdin-Independent C3 Nephritic Factors Provide Insight for Properdin-Inhibiting Therapy

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Michels, Marloes, Amalia Children's Hospital, Radboud university medical center, Nijmegen, Netherlands
  • Van De Kar, Nicole, Amalia Children's Hospital, Radboud university medical center, Nijmegen, Netherlands
  • van den Bos, Ramon Marijs, Utrecht University, Utrecht, Netherlands
  • Van der velden, Thea J., Amalia Children's Hospital, Radboud university medical center, Nijmegen, Netherlands
  • van Kraaij, Sanne, Radboud university medical center, Nijmegen, Netherlands
  • Sarlea, Sebastian Andrei, Amalia Children's Hospital, Radboud university medical center, Nijmegen, Netherlands
  • Gracchi, Valentina, University Medical Center Groningen, Groningen, Netherlands
  • Oosterveld, Michiel Js, Emma Children's Hospital, Amsterdam University Medical Center, Amsterdam, Netherlands
  • Volokhina, Elena, Amalia Children's Hospital, Radboud university medical center, Nijmegen, Netherlands
  • Van den heuvel, Lambertus P.W.J., Amalia Children's Hospital, Radboud university medical center, Nijmegen, Netherlands

Group or Team Name

  • on behalf of the COMBAT consortium
Background

C3 glomerulopathy (C3G) is a severe renal disorder caused by dysregulation of the alternative complement pathway and is characterized by depositions of C3 fragments in the glomeruli. C3 nephritic factors (C3NeFs) are found in the blood of more than half of C3G patients. These autoantibodies recognize the alternative pathway C3 convertase and prolong its activity. C3NeFs can be dependent or independent of the complement regulator properdin for their convertase-stabilizing function. However, studies to determine the properdin-dependency of C3NeFs are rare and not part of routine patient investigations. Until recently, only supportive treatments for C3G were available. Complement-directed therapies are now being investigated. We hypothesized that patients with properdin-dependent C3NeFs may benefit from properdin-inhibiting therapy to normalize convertase activity.

Methods

Therefore, we have validated two hemolytic assays to distinguish between properdin-dependent and properdin-independent C3NeFs by assessing the convertase activity and stability in absence of properdin. The first assay measures convertase stabilization by patient immunoglobulins in properdin-depleted serum. The second measures convertase stabilization directly in patient serum supplemented with the Salp20, a properdin-blocking agent.

Results

Blood samples from 13 pediatric C3G patients positive for C3NeF were tested for convertase stabilization in absence of properdin. Three patients presented with properdin-dependent C3NeFs as no C3NeF activity was observed in absence of properdin, whereas the C3NeF activity of the other 10 patients was independent of properdin. In the samples of the patients with properdin-dependent C3NeFs, addition of the properdin-blocking agent Salp20 normalized the convertase activity profile.

Conclusion

These results indicate that inhibition of properdin in patients with properdin-dependent C3NeFs can normalize alternative pathway convertase activity and could represent a novel therapy. Our assays provide a tool for identifying C3G patients who may benefit from properdin-inhibiting therapy and should be incorporated into standard C3G laboratory investigations.