Epidemiology and Pathophysiology of Glomerular C4d Staining in Native Kidney Biopsies.

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.