Glomerular membrane attack complex is not a reliable marker of ongoing C5 activation in lupus nephritis

Abstract

Complement plays an important role in the pathogenesis of lupus nephritis (LN). With the emergence of therapeutic complement inhibition, there is a need to identify patients in whom complement-driven inflammation is a major cause of kidney injury in LN. Clinical and histopathological data were obtained retrospectively from 57 biopsies with class III, IV, and V LN. Biopsies were stained for complement components C9, C5b-9, C3c, and C3d and for the macrophage marker CD68. C9 and C5b-9 staining were highly correlated ( r = 0.92 in the capillary wall). C5b-9 staining was detected in the mesangium and/or capillary wall of both active and chronic proliferative LN in all but one biopsy and in the capillary wall of class V LN in all biopsies. C5b-9 staining intensity in the tubular basement membrane correlated with markers of tubulointerstitial damage, and more intense capillary wall C5b-9 staining was significantly associated with nonresponse to conventional treatment. Glomerular C5b-9 staining intensity did not differ between active and chronic disease; in contrast, C3c and CD68 staining were associated with active disease. Evaluation of serial biopsies and comparison of staining in active and chronic LN demonstrated that C5b-9 staining persisted for months to years. These results suggest that C5b-9 staining is almost always present in LN, resolves slowly, and is not a reliable marker of ongoing glomerular C5 activation. This limits the utility of C5b-9 staining to identify patients who are most likely to benefit from C5 inhibition.

Eculizumab deposits in vessel walls in thrombotic microangiopathy

“…Although our case numbers may be too small to draw definitive conclusions, it appears that the intensity of IgG2/ IgG4 and k IF staining (and thus eculizumab deposition) is brighter in cases with active ongoing TMA, as opposed to cases with no morphologic evidence of TMA (cases in remission after treatment). In contrast, C5b-9 staining intensity and distribution showed no correlation with disease activity, which is similar to what was observed by Herlitz et al 16 in C3GN biopsies 1 year after eculizumab therapy, as well as in biopsy specimens of persons with lupus nephritis, 18 in which similar C5b-9 staining was observed in both active and inactive disease cases. These findings could either represent slow tissue clearance as a result of a prolonged half-life of C5b-9 when bound to extracellular matrix or could indicate incomplete complement inhibition by eculizumab.…”

Complement activity is regulated in C3 glomerulopathy by IgG–factor H fusion proteins with and without properdin targeting domains

“…We speculate that our agents, through conformational changes, may efficiently interact with both fluid-phase and C3d persisted for weeks 16 . Also, glomerular C3d is persistent in lupus nephritis 26 . This is likely to reflect its covalent interaction with glomerular surfaces.…”

Clinical promise of next-generation complement therapeutics

“…Indeed, more focus should be placed on monitoring dynamic changes in complement biomarkers and on ratios of activated versus total protein, rather than absolute protein levels in fluids or tissues, since the latter are merely snapshots that can misguide treatment by causing clinicians to overlook underlying pathogenic mechanisms 217,218 . The varied plasma half-lives of complement activation fragments (C3b, iC3b, C3dg and C3a/C5a) and their differential clearance rates from tissues should be taken into account when ongoing disease activity is measured by immunoassays that quantitate specific activation fragments or complexes (for example, C5b-9) 218,219 . In this direction, the advent of high-dimensional multi-omics technologies, such as single-cell RNA sequencing (RNAseq) and mass cytometry, coupled with the availability of powerful genome editing tools such as the CRISPR-Cas9 system, are expected to leverage complement diagnostics for identifying new therapeutic targets and informing complement intervention in new and unexplored indications 220,221 .…”