Epidemiology and Pathophysiology of Glomerular C4d Staining in Native Kidney Biopsies

Abstract

IntroductionRoutine 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.MethodsWe retrospectively evaluated C4d staining in formalin-fixed paraffin-embedded sections from 519 native kidney biopsies (bx) with and without glomerular disease.ResultsStrong 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.ConclusionBased 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.

Complete remission of nephrotic syndrome in a young woman with anti-LRP2 nephropathy after immunosuppressive therapy

“…The mechanism of nephrotic proteinuria in anti-LRP2 nephropathy is not known. Drachenberg et al reported that C4d was negative in MCD, but positive in immune-complex glomerulonephritis [10]. Therefore, in our patient, the presence of C4d and IgG along the capillary loop does not seem to support MCD.…”

Clinicopathologic Features of Infection-Related Glomerulonephritis with IgA Deposits: a French Nationwide Study

“…A recent study reported 26.4% of capillary wall C4d staining in IgAN, correlated to endocapillary proliferation, rendering C4d inaccurate for differential diagnosis with IRGN-IgA 31. Some authors hypothesized that IgAN can develop secondary to Staphylococcus aureus infection 31. However, this hypothesis does not explain the pathophysiology of IRGN-IgA due to other pathogens (25% of our cohort).IgA deposits due to liver disease represent another differential diagnosis for IRGN-IgA.…”

“…Interestingly, none of these 16 biopsies presented diffuse capillary wall C4d staining, leading us to speculate that the presence of capillary wall C4d staining could help to distinguish both entities.However, C4d staining was previously observed in some cases of IgAN, corresponding to the activation of lectin pathway of complement, and predictive of a poorer prognosis 30. A recent study reported 26.4% of capillary wall C4d staining in IgAN, correlated to endocapillary proliferation, rendering C4d inaccurate for differential diagnosis with IRGN-IgA 31. Some authors hypothesized that IgAN can develop secondary to Staphylococcus aureus infection 31.…”

Relevance of glomerular C4d deposition in pediatric patients with Henoch-Schönlein Purpura compared to IgA nephritis

“…On the other hand, our single centre patients represent a relatively homogenous group in terms of diagnosis and treatment. We also have to acknowledge that C4d-staining might vary as already shown for IgAN patients (23) and therefore one has to be careful with respect to the conclusions drawn from these data. However, we tried to take care of this problem by staining all biopsies at one time point and by multiple separate analyses of the staining.…”