OP0043 RENAL TUBULAR COMPLEMENT C9 DEPOSITION IS ASSOCIATED WITH RENAL TUBULAR DAMAGE AND FIBROSIS IN LUPUS NEPHRITIS

Abstract

Background:Tubulointerstitial damage in lupus nephritis (LN) is a strong predictor of progression to chronic kidney disease and end stage renal disease (ESRD). While prior studies showed complement activation mediates glomerular injury (1), the role of complement in renal tubular damage has not been evaluated.Objectives:To investigate the association between complement activation and tubulointerstitial fibrosis. Specifically, to study the role of tubular complement C9 deposition as a marker of tubular damage and fibrosis in LN.Methods:LN biopsies stored in the pathology department between July 2014 to July 2016 were evaluated. 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) as a marker of the terminal complement activation. C3 glomerulopathy was used as a positive control, and normal kidney from resected tumor served as a negative control. Tubular basement membrane C9 staining intensity were analyzed on a semi-quantitative scale from 0 to 3 by a renal pathologist. The degree of Interstitial fibrosis/tubular atrophy was categorized as low (0–10%), medium (11–20%), or high (≥21%). Clinical parameters were assessed at the time of biopsy and 6 months post biopsy.Results:Renal biopsies from 30 LN were studied, 23 (77%) of which had proliferative LN (Table). There were 24 (80%) women, mean (SD) age 33 (12) years. Positive tubular C9 staining (C9+) was observed in 7 (23%) biopsies. There was no significant difference in eGFR at renal biopsy between the two groups. At the time of renal biopsy, C9+ patients had significantly higher proteinuria, compared to C9- patients: median (IQR) 6.2g (3.3-13.1) vs. 2.4g (1.3-4.6), p<0.01. The differences persisted at 6 months after induction therapy with cyclophosphamide, cellcept or clinical trial drug: 1.08g (1.0-8.3) in C9+ vs. 0.68g (0.2-2.1) in C9- patients, p=0.06 Tubular C9 deposition was associated with interstitial fibrosis: 3 out of 7 (42.9%) had severe interstitial fibrosis vs. none in the C9- group, p=<0.01. Higher proportion of C9+ patients had moderate NIH Chronicity index: 3 out of 7 (42.9%) vs 2 out of 23 (8.7%) in the C9- group, p=0.07.Table.Comparisons of C9+ and C9- biopsiesConclusion:Tubular C9 deposition is significantly associated with proteinuria, interstitial fibrosis and increased chronicity which predict progression to ESRD and mortality. Complement activation in the tubules may be linked to proteinuria and more studies are needed to elucidate its mechanism in tubulointerstitial damage in LN.