Soluble CR1 therapy improves complement regulation in C3 glomerulopathy

Yuzhou Zhang, Carla M. Nester, Danniele G. Holanda, Henry C. Marsh, Russell A. Hammond, Lawrence J. Thomas, Nicole C. Meyer, Lawrence G. Hunsicker, Sanjeev M Sethi, Richard J H Smith

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are widely recognized subtypes of C3 glomerulopathy. These ultra-rare renal diseases are characterized by fluid-phase dysregulation of the alternative complement pathway that leads to deposition of complement proteins in the renal glomerulus. Disease triggers are unknown and because targeted treatments are lacking, progress to end stage renal failure is a common final outcome. We studied soluble CR1, a potent regulator of complement activity, to test whether it restores complement regulation in C3 glomerulopathy. In vitro studies using sera from patients with DDD showed that soluble CR1 prevents dysregulation of the alternative pathway C3 convertase, even in the presence of C3 nephritic factors. In mice deficient in complement factor H and transgenic for human CR1, soluble CR1 therapy stopped alternative pathway activation, resulting in normalization of serum C3 levels and clearance of iC3b from glomerular basement membranes. Short-term use of soluble CR1 in a pediatric patient with end stage renal failure demonstrated its safety and ability to normalize activity of the terminal complement pathway. Overall, these data indicate that soluble CR1 re-establishes regulation of the alternative complement pathway and provide support for a limited trial to evaluate soluble CR1 as a treatment for DDD and C3GN.

Original languageEnglish (US)
Pages (from-to)1820-1829
Number of pages10
JournalJournal of the American Society of Nephrology
Volume24
Issue number11
DOIs
StatePublished - Nov 1 2013

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Membranoproliferative Glomerulonephritis
Alternative Complement Pathway
Glomerulonephritis
Chronic Kidney Failure
Complement C3 Nephritic Factor
Alternative Pathway Complement C3 Convertase
Complement C3b
Kidney
Glomerular Basement Membrane
Complementary Therapies
Rare Diseases
Serum
Complement System Proteins
Therapeutics
Pediatrics
Safety

ASJC Scopus subject areas

  • Nephrology

Cite this

Zhang, Y., Nester, C. M., Holanda, D. G., Marsh, H. C., Hammond, R. A., Thomas, L. J., ... Smith, R. J. H. (2013). Soluble CR1 therapy improves complement regulation in C3 glomerulopathy. Journal of the American Society of Nephrology, 24(11), 1820-1829. https://doi.org/10.1681/ASN.2013010045

Soluble CR1 therapy improves complement regulation in C3 glomerulopathy. / Zhang, Yuzhou; Nester, Carla M.; Holanda, Danniele G.; Marsh, Henry C.; Hammond, Russell A.; Thomas, Lawrence J.; Meyer, Nicole C.; Hunsicker, Lawrence G.; Sethi, Sanjeev M; Smith, Richard J H.

In: Journal of the American Society of Nephrology, Vol. 24, No. 11, 01.11.2013, p. 1820-1829.

Research output: Contribution to journalArticle

Zhang, Y, Nester, CM, Holanda, DG, Marsh, HC, Hammond, RA, Thomas, LJ, Meyer, NC, Hunsicker, LG, Sethi, SM & Smith, RJH 2013, 'Soluble CR1 therapy improves complement regulation in C3 glomerulopathy', Journal of the American Society of Nephrology, vol. 24, no. 11, pp. 1820-1829. https://doi.org/10.1681/ASN.2013010045
Zhang Y, Nester CM, Holanda DG, Marsh HC, Hammond RA, Thomas LJ et al. Soluble CR1 therapy improves complement regulation in C3 glomerulopathy. Journal of the American Society of Nephrology. 2013 Nov 1;24(11):1820-1829. https://doi.org/10.1681/ASN.2013010045
Zhang, Yuzhou ; Nester, Carla M. ; Holanda, Danniele G. ; Marsh, Henry C. ; Hammond, Russell A. ; Thomas, Lawrence J. ; Meyer, Nicole C. ; Hunsicker, Lawrence G. ; Sethi, Sanjeev M ; Smith, Richard J H. / Soluble CR1 therapy improves complement regulation in C3 glomerulopathy. In: Journal of the American Society of Nephrology. 2013 ; Vol. 24, No. 11. pp. 1820-1829.
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