Background/Purpose:

LN is characterized by deposition of immune complexes in the kidney. Activation of the classical complement pathway by dsDNA is believed to play a role in its pathogenesis.  The relative importance of C5a generation versus MAC involvement in tissue injury remains uncertain. We study immunohistochemistry staining for C9 in renal biopsies as a marker for intensity of kidney damage and clinical response to therapy.

Methods:

Chromogenic immunohistochemistry was performed on formalin-fixed, paraffin-embedded, 4-µm human renal biopsy sections using unconjugated, murine anti-human Complement C9 (Hycult Biotech, clone X197) from SLE patients who fulfill 4 ACR or SLICC criteria. Positive control is C3 glomerulopathy and negative control is normal kidney. Clinical parameters assessed at time of biopsy and 6 months. Student t-test, Fisher’s exact test, and logistic regression were performed in SAS.

Results:

30 renal biopsies were obtained from SLE patients with LN Class II (2), III (5), IV (8), V (5), III+V (8) and IV+V (2) This study included 24 women and 6 men, mean age 32.9 ± 12.1 years, with 4 Asians, 9 Blacks, 11 Hispanics and 6 Caucasians. 13/30 (43.3%) biopsies stained positive for glomerular C9 (Figure 1). Patients with +C9 have significantly higher systolic/diastolic BP, trend towards lower C3, and male gender; known predictors of poor renal outcomes (Table 1). There was no significant difference for ISN/RPN class, activity or chronicity indices between +C9 vs. –C9 groups. Five (45.5%) of 11 patients with +C9 did not respond to therapy at 6 months (defined as <50% reduction in proteinuria), compared with 2/15 (13.3%) patients with –C9. No difference in induction or maintenance therapy and compliance to therapy was found between +C9 and –C9 groups. +C9 patients were significantly more likely to be a non-responder at 6 months (OR=5.3, 95% CI 0.8, 36.4) compared to –C9 patients. After adjusting for systolic BP, compliance to treatment and proteinuria at time of biopsy in a multivariate logistic model, +C9 patients remain more likely to be non-responders (OR=4.3, 95% CI 0.3, 65.2).

Conclusion:

This study demonstrates that MAC deposition is a biomarker for more intense disease and that targeting C5a may be insufficient for controlling inflammation and damage in LN. MAC staining may be useful in routine IF studies of suspected or known lupus renal biopsies to identify patients at risk for aggressive and refractory disease and who may be candidates for novel therapies targeting terminal complement pathway.