C3 deposition glomerulopathy due to a functional Factor H defect

Two female siblings (patient 1: 12 6/12; Patient 2: 7 3/12 years old) of consanguineous parents, presented with hematuria and proteinuria at five years (Patient 1) and six months (Patient 2) of age, respectively. Clinical examination, renal ultrasonography and laboratory analyses resulted normal, and both patients were normotensive. Detailed complement analyses, however, demonstrated activation of the alternative complement pathway reflected by decreased C3 and Factor B (FB), and increased C3d, while C4 was normal. The Factor H (CFH) gene (CFH) had a deletion of a single amino acid (Lysine) in position 224 (DK224) within its complement regulatory region in short consensus repeat 4 (SCR 4). In addition, both patients and also the healthy mother were C3 nephritic factor (C3NeF) positive. Renal biopsy in Patient 1 at five years of age prior to therapy (biopsy 1.1) was initially interpreted as membranoproliferative glomerulonephritis type II/dense deposit disease (MPGN II/DDD). Chronic treatment with fresh frozen plasma (FFP) was initiated in both patients (10-15mL FFP/kg body weight/14 d). A follow- up biopsy of Patient 1 after two years of periodical FFP-infusion (biopsy 1.2) showed no disease progression as compared to the pre-treatment biopsy. This is to our knowledge the first report of successful long-term treatment with periodical FFP-infusion of such patients. Renal biopsy of Patient 2 (Biopsy 2) in whom no pre-treatment biopsy had been performed confirmed both the same diagnosis and the level of disease severity as observed in Patient 1. Furthermore, in light of the recent description of patients with a phenotypical spectrum of glomerular pathology termed glomerulonephritis C3 ( we suggest the term 'C3 deposition glomerulopathy (C3DG)' which more precisely describes the pathological changes in the glomerulus than 'glomerulonephritis C3 (GN C3)' does.) which is also caused by dysregulation of the alternative complement pathway, including complement deposition within the glomerular basement membrane (GBM), the subendothelial and mesangial space, the diagnosis of the two patients could be specified as fitting into this disease group. In summary, chronic treatment with periodical FFP-infusion was successful in preventing disease progression in two patients with C3 deposition glomerulopathy (C3DG) caused by alternative complement pathway dysregulation because of dysfunctional CFH and C3NeF.