Abstract: TH-PO018

The Role of Complement C9 as a Marker for Therapeutic C5 Blockade in Lupus Nephritis

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Wilson, Hannah R., Imperial College Lupus Centre, Imperial College Healthcare NHS Trust, London, United Kingdom
  • Cook, H. Terence, Imperial College Lupus Centre, Imperial College Healthcare NHS Trust, London, United Kingdom
  • Gilmore, Alyssa C, Imperial College Lupus Centre, Imperial College Healthcare NHS Trust, London, United Kingdom
  • Medjeral-Thomas, Nicholas R, Imperial College Lupus Centre, Imperial College Healthcare NHS Trust, London, United Kingdom
  • Trivedi, Pritesh, Imperial College Lupus Centre, Imperial College Healthcare NHS Trust, London, United Kingdom
  • Seyb, Kathleen I, Ra Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
  • Farzaneh-Far, Ramin, Ra Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
  • Cairns, Tom, Imperial College Lupus Centre, Imperial College Healthcare NHS Trust, London, United Kingdom
  • Lightstone, Liz, Imperial College Lupus Centre, Imperial College Healthcare NHS Trust, London, United Kingdom
  • Pickering, Matthew C., Imperial College Lupus Centre, Imperial College Healthcare NHS Trust, London, United Kingdom
Background

Complement plays an important role in the pathogenesis of lupus nephritis (LN) and there are reports of therapeutic benefit with eculizumab, a C5 inhibitor. However, LN can also develop in complement-deficient individuals. With the emergence of therapeutic C5 inhibition, there is a need to identify patients in whom complement-driven inflammation, attributable to C5a, C5b-9, or both, is a major cause of kidney injury in LN.

Methods

Clinical and histopathological data from 54 patients with class III, IV and V LN were obtained retrospectively. Staining for C9, C5b-9, C3c and CD68 was performed and intensity assessed. Response was defined using urine protein-creatinine ratio and estimated glomerular filtration rate.

Results

C9 staining was equivalent to C5b-9 staining. C9 was detected in the mesangium of both active and chronic proliferative (class III and IV) LN in the majority of patients and in the capillary wall of class V LN in all patients. C9 staining intensity in the tubular basement membrane correlated with creatinine levels at the time of biopsy and with markers of tubulo-interstitial damage. C9 staining intensity did not correlate with C3c staining intensity or glomerular CD68 count. C9 staining also did not correlate with serological markers of activity, however C3c and CD68 staining did. Although not statistically significant, a low C9 staining intensity appears to indicate a greater chance of complete remission in active disease.

Conclusion

The widespread presence of glomerular C9 in LN supports a role for the C5b-9 membrane attack complex in renal injury. Importantly, the lack of correlation with C3c intensity suggests that the kinetics of glomerular C9 and C3c staining differ. Understanding the kinetics of complement deposition will be important in identifying patients most likely to benefit from C5 inhibition.

Funding

  • Commercial Support