H1(T)
COMPLEMENT FACTOR H-RELATED PROTEIN 5 (CFHR5) DEFICIENCY IS A
RISK FACTOR FOR CHRONIC RENAL DISEASE FOLLOWING ACUTE POSTSTREPTOCOCCAL GLOMERULONEPHRITIS
Vernon, K1, Goicoechea de Jorge, E1, Rose, K1, Hall, A2, Rigby, E3, Hangartner, R4, Cook,
H1, Koziell, A3, 5, Pickering, M1
1
Centre for Complement and Inflammation Research, Division of Immunology and
Inflammation, Faculty of Medicine, Imperial College, London, 2Department of
Immunology, Imperial College Healthcare NHS Trust, London, 3Paediatric Nephrology,
4
Cellular Pathology and 5Department of Nephrology and Transplantation, Guy’s and St
Thomas’ NHS Foundation Trust, London
Acute post-streptococcal glomerulonephritis (APSGN) is a common cause of acute nephritis in
children. Transient hypocomplementaemia and complete recovery are characteristic with only a
minority of affected individuals developing chronic disease. The risk factors for chronic disease
are unknown.
We describe a previously healthy young girl who developed persistent renal disease and
hypocomplementaemia following an episode of APSGN. Remarkably, plasma C3 levels remain
profoundly depressed 5½ years after the episode of APSGN. Renal biopsy 1 year after
presentation demonstrated florid isolated glomerular C3 deposition, membranoproliferative
changes and sub-endothelial and occasional sub-epithelial glomerular basement membrane
deposits, features consistent with C3 glomerulopathy. Repeat renal biopsy 2 years after
presentation showed similar but more severe changes together with the appearance of mesangial
and intra-membranous glomerular basement membrane deposits.
Since C3 glomerulopathy is associated with complement dysregulation we sequenced the
complement genes: CFH, CFI, CD46, factor B, C3 and CFHR5. This revealed a heterozygous
single nucleotide insertion in exon 4 of the CFHR5 gene resulting in the generation of a
premature stop codon. This change was not present in over 100 healthy Caucasian controls.
Plasma CFHR5 levels were significantly reduced in both the index case and her healthy mother
who also harboured the CFHR5 mutation in heterozygosity. No evidence of C3 nephritic factor
activity was demonstrable in the patient’s serum and the half-life of exogenous C3 in the
patient’s serum was normal in vitro.
We speculate that heterozygous deficiency of CFHR5 is a risk factor for the development of C3
glomerulopathy following a renal insult such as APSGN. Our index case was healthy prior to
the development of APSGN. In contrast to the majority of cases of APSGN she developed
chronic renal disease and persistently low C3 levels. Notably, her mother who carries the same
mutation has no evidence of renal disease indicating that heterozygous deficiency of CFHR5 is
not sufficient in itself to cause C3 glomerulopathy. We conclude that CFHR5 deficiency is a
risk factor for chronic renal disease following APSGN.