ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: PO2237

Targeting of Factor D in Cfh-/- Mice Does Not Relieve C3 Glomerulopathy due to the Action of C3(H2O)

Session Information

Category: Pathology and Lab Medicine

  • 1601 Pathology and Lab Medicine: Basic

Authors

  • Zhang, Yuzhou, Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, Iowa, United States
  • Keenan, Adam C., Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, Iowa, United States
  • Dai, Dao-Fu, Department of Pathology, University of Iowa, Iowa City, Iowa, United States
  • May, Kristofer S., Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, Iowa, United States
  • Pitcher, Gabriella R., Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, Iowa, United States
  • Taylor, Ronald P., University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Smith, Richard J., Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, Iowa, United States
Background

C3 glomerulopathy (C3G) is an ultra-rare kidney disease defined by underlying complement dysregulation and characterized by complement C3 deposition on kidney biopsy. Dysregulation of the alternative pathway (AP) is fundamental to disease expression, although terminal pathway dysregulation is also common. Treatment of C3G with eculizumab is unsuccessful in the majority of patients, consistent with the fact that eculizumab targets the terminal complement cascade while leaving up-stream C3 complement dysregulation untouched. Of up-stream targets, factor D (FD) is appealing because it circulates in the plasma at low concentrations and has a single function, to cleave its substrate, factor B, to generate C3 convertases of the alternative complement pathway. Mice with a targeted deletion of factor H (FH; Cfh-/- mice) develop features of C3 glomerulopathy (C3G).

Methods

To assess the impact of FD inhibition, we studied Cfh-/-;Cfd-/- mice. After crossing the Cfd-/- and Cfh-/- mice, Cfh+/-;Cfd+/- progeny were backcrossed to C57BL/6 for 10 generations. Littermates of Cfh-/-, Cfd-/-, Cfh-/-;Cfd-/- and wildtype were used for assessing complement dysregulation and renal pathology.

Results

The C3G phenotype in the Cfh-/- mouse is not rescued by removing FD. Instead, Cfh-/-;Cfd-/- mice develop a subtype of C3G and nephrogenic diabetes insipidus. We used serum from the Cfh-/-;Cfd-/- mouse to show that residual AP function is present when both FD and FH are missing and that hemolytic activity is increased in vitro and in vivo due to the action of C3(H2O). Therefore, uncontrolled tick-over leads to slow activation of the AP in the Cfh-/-;Cfd-/- mouse. While a tiny amount of FD suffices to activate complement, a minimal threshold of FH is needed to prevent tissue deposition of C3 in the absence of FD.

Conclusion

These findings suggest that efforts to block AP activity by targeting FD may lead to unanticipated outcomes in subgroups of C3G patients. Sustained complete and persistent FD blockade may be difficult to maintain, and due to the action of C3(H20) might not completely suppress complement activation; substantial breakthrough complement activation may then occur as even minuscule amounts of free FD become available.

Funding

  • NIDDK Support