Research Article: Acute Presentation and Persistent Glomerulonephritis Following Streptococcal Infection in a Patient With Heterozygous Complement Factor H–Related Protein 5 Deficiency

Date Published: July 1, 2012

Publisher: W.B. Saunders

Author(s): Katherine A. Vernon, Elena Goicoechea de Jorge, Angela E. Hall, Veronique Fremeaux-Bacchi, Timothy J. Aitman, H. Terence Cook, Robert Hangartner, Ania Koziell, Matthew C. Pickering.


Acute poststreptococcal glomerulonephritis is a common cause of acute nephritis in children. Transient hypocomplementemia and complete recovery are typical, with only a minority developing chronic disease. We describe a young girl who developed persistent kidney disease and hypocomplementemia after a streptococcal throat infection. Kidney biopsy 1 year after presentation showed isolated glomerular complement C3 deposition, membranoproliferative changes, and subendothelial, intramembranous and occasional subepithelial electron-dense deposits consistent with C3 glomerulopathy. Complement gene screening revealed a heterozygous single nucleotide insertion in exon 4 of the complement factor H–related protein 5 gene (CFHR5), resulting in a premature stop codon. This variant was not detected in 198 controls. Serum CFHR5 levels were reduced. The mother and sister of the index patient were heterozygous for the sequence variant, with no overt evidence of kidney disease. We speculate that this heterozygous CFHR5 sequence variant is a risk factor for the development of chronic kidney disease after streptococcal infection.

Partial Text

A previously healthy 7-year-old Caucasian female presented with a 10-day history of lethargy, fever, sore throat, and cough associated with abdominal pain, vomiting, and dark colored urine. Mild periorbital edema was accompanied by abnormal urinalysis results (protein [3+], blood [3+]). Results of investigations included the following values: serum urea nitrogen, 50.1 mg/dL (17.9 mmol/L); creatinine, 0.98 mg/dL (87 μmol/L); hemoglobin, 10.9 g/dL (109 g/L); C-reactive protein, 77 mg/L; C3, 0.36 mg/mL (0.36 g/L; reference range, 0.75-1.65); C4, 0.29 mg/mL (0.29 g/L; reference range, 0.11-0.43); and urine protein-creatinine ratio, 5,221 mg/g. Both serum anti-streptolysin O (>200 U/mL) and anti-DNase antibody titers (360 U/mL) were elevated. Kidney ultrasound showed 8.3-cm kidneys with loss of corticomedullary differentiation.

CFHR5 is a member of the CFH family of proteins encoded within the regulators of complement activation gene cluster on chromosome 1.10 CFHR5 has been shown to have complement-regulatory function in vitro11 and to colocalize with complement deposits within the kidney in a variety of glomerular pathologic states.12 The biological role of CFHR5 is unclear, but it is postulated to have a physiologic role in the processing of complement within the kidney.13 This hypothesis has derived from reports of genetic variation in CFHR5 and susceptibility to kidney disease. A heterozygous CFHR5 mutation has been shown to be associated with the development of familial C3 glomerulonephritis in individuals of Cypriot ancestry,13 and allelic variants of CFHR5 have been associated with dense deposit disease.14 Previously published evidence that CFHR5 interacts with glomerular complement12,13 suggests that this phenomenon contributed to the decrease in serum CFHR5 levels in the index case. Consistent with this hypothesis was our observation that glomerular CFHR5 was easily detectable in kidney biopsy specimens from the index case, median serum CFHR5 levels were low in individuals with C3 glomerulonephritis, and serum CFHR5 level in the index patient was lower than levels in other family members with the sequence variant, but no kidney disease. An interesting additional insight based on these data is that serum CFHR5 levels may be a useful biomarker of glomerular C3 deposition.