Epidemiology and Pathophysiology of Glomerular C4d Staining in Native Kidney Biopsies

Cinthia B Drachenberg; John C Papadimitriou; Preeti Chandra; Abdolreza Haririan; Susan Mendley; Matthew R Weir; Mario F Rubin

doi:10.1016/j.ekir.2019.07.015

Epidemiology and Pathophysiology of Glomerular C4d Staining in Native Kidney Biopsies

Kidney Int Rep. 2019 Jul 30;4(11):1555-1567. doi: 10.1016/j.ekir.2019.07.015. eCollection 2019 Nov.

Authors

Cinthia B Drachenberg¹, John C Papadimitriou¹, Preeti Chandra², Abdolreza Haririan², Susan Mendley³, Matthew R Weir², Mario F Rubin²

Affiliations

¹ Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
² Department of Medicine, Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
³ Department of Pediatrics, Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Abstract

Introduction: Routine C4d staining in renal transplantation has stimulated its use in kidney biopsies with glomerulonephritis (GN). Methodical description on staining patterns in the native kidney is not available.

Methods: We retrospectively evaluated C4d staining in formalin-fixed paraffin-embedded sections from 519 native kidney biopsies (bx) with and without glomerular disease.

Results: Strong C4d staining was consistently present in immune-complex GN, including lupus nephritis (LN) (n = 68), membranous GN (n = 24), membranoproliferative glomerulonephritis (MPGN) pattern (n = 22), fibrillary GN (n = 3), and proliferative GN with monoclonal IgG (n = 3). C4d stained all cases of postinfectious GN (n = 7) amyloidosis (n = 20) and C1q GN (n = 3). In contrast, IgA nephropathy (IgAN) (n = 34), was negative in 62% of bx, with the rest staining variably. The E1 Oxford classification score correlated with capillary wall C4d staining (P = 0.05). C4d marked the glomerular and arteriolar lesions in thrombotic microangiopathy (TMA; n = 16), the glomerular sclerotic segments in focal segmental glomerulosclerosis (FSGS; n = 77), and marked areas of necrosis in crescentic GN (n = 21). In diabetic glomerulopathy (n = 70), C4d marked advanced insudative lesions but was negative otherwise. C4d weakly stained the mesangium, or was negative in normal biopsies (n = 13), minimal change disease (MCD; n = 21), thin basement membrane disease (n = 20), Alport (n = 3), IgM nephropathy (n = 2), C3 glomerulopathy (n = 5), acute interstitial nephritis (n = 12), acute tubular necrosis (n = 22), ischemic glomerulopathy/nephrosclerosis (n = 23), and other miscellaneous processes (n = 14). Staining in tubular basement membranes and peritubular capillaries was most common in lupus.

Conclusion: Based on reliable staining in lupus and membranous GN, C4d staining is potentially useful as a screening and diagnostic tool, if only paraffin-embedded tissue is available. Knowledge of C4d staining patterns in normal and pathological tissues enhances its diagnostic value.

Keywords: IgA nephropathy; complement deposition; diabetes mellitus; glomerulonephritis; immune deposits; lupus nephritis; membranous glomerulopathy.