A novel CFHR5 mutation associated with C3 glomerulonephritis in a Turkish girl

Abstract

C3 glomerulopathy defines a subgroup of membranoproliferative glomerulonephritis (MPGN) characterized by complement 3 (C3)-positive, immunoglobulin-negative deposits in immunofluorescence microscopy. It comprises 3 clinical conditions: dense deposit disease, C3 glomerulonephritis, and complement factor H-related 5 (CFHR5) nephropathy. Mutations in genes encoding regulatory proteins of the alternative complement pathway have been described. A 16-year-old girl was admitted to the hospital due to periorbital edema. Nephrotic syndrome accompanied by low C3 level was diagnosed. Renal biopsy showed MPGN in light microscopy, only C3 deposits in immunofluorescence microscopy, and subendothelial electron dense deposits and capillary basement membrane thickening with double contour formation in electron microscopy. C3 nephritic factor and anti complement factor H antibody were negative. Complement factor H level was normal. Genetic screening showed a novel heterozygous p.Cys269Arg variation in the CFHR5 gene without any mutation in CFH and CFI genes. Eculizumab therapy was started but was unsuccessful at 10 months of follow-up. We have identified a novel heterozygous variation in CFHR5-related nephropathy presenting with nephrotic syndrome and persistently low C3 level, thus expanding the genetic and phenotypic spectrum of the disease. Eculizumab seems to be ineffective in this subtype.

C3 glomerulopathy in children: Is there still a place for anti‐cellular immunosuppression?

“…There are several case reports published in which eculizumab, C5 inhibitor, the first anti‐complement agent on the market, was used off‐label in patients with C3GP. Although clinical improvement was reported in the majority of these, it could, however, be biased if investigators would have published mainly successful treatment trials. Namely, there have been very few large series of eculizumab‐treated C3GP patients reported so far, particularly in children.…”

“…Uncontrolled studies using anti-cellular immunosuppression in C3GP patients, aimed at reducing antibodyproducing cells, were more prone to failure than efficacy of such treatment, 3 while eculizumab, even though it seemed very promising, did not give the expected results. In the majority of case reports published, clinical improvement with eculizumab was, however, reported, [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] but can be said to be biased by reporting mostly positive results. On the other hand, a closer look at, though very few (especially in children), large series of eculizumab-treated C3GP patients describe various results.…”

Does complement Factor H-Related protein 5 Nephropathy (Troodos Nephropathy) protect from rickettsial infections?

“…More recently, the emerging role of Complement Factor-H Related proteins (CFHRs) in complement-mediated diseases has attracted increased interest with the identification of hybrid CFH/CFHR1 and CFH/CFHR3 genes causing aHUS [26][27][28]. Subsequently, the identification of CHFR mutations (internal duplications) and hybrid CFHR genes (CFHR3/ CFHR1 and CFHR2/CFHR5) causing familial C3 glomerulopathies has further intensified this interest [1,[29][30][31][32][33][34].…”

Complement related kidney diseases: Recurrence after transplantation

“…CFHR family gene mutations[94], deletions[95], duplication[96] and hybrid genes[97] have been reported in patients with C3Gs either in isolated patients or family groups.…”