title: Treatment with human complement factor H rapidly reverses renal complement deposition in factor H-deficient mice.
abstract: Total deficiency of complement factor H (CFH) is associated with dense deposit disease and atypical hemolytic uremic syndrome. CFH is the major regulator of the alternative pathway of complement activation and its complete deficiency results in uncontrolled C3 activation through this pathway and secondary C3 deficiency. Plasma infusion, as a source of CFH, has been used with variable success to treat renal disease associated with its deficiency. However, the risks of volume and protein overload limit this therapeutic approach. In this study, we investigated the efficacy of a purified human CFH (hCFH) preparation in Cfh-gene knockout mice. These mice spontaneously develop both secondary plasma C3 deficiency and a renal abnormality characterized by massive accumulation of C3 along the glomerular basement membrane. The renal lesion is analogous to human dense deposit disease. Treatment of knockout mice with hCFH resulted in rapid normalization of plasma C3 levels and resolution of the glomerular basement membrane C3 deposition. Long-term treatment of mice with hCFH was not possible because of the development of an immune response against hCFH. Hence, we suggest that hCFH can be an effective alternative therapy to plasma infusions in patients with renal disease associated with CFH deficiency.
authors.affiliation: Rheumatology Section, Imperial College, London, UK.
authors.forename: Fadi
authors.initials: F
authors.lastname: Fakhouri
authors.forename: Elena Goicoechea
authors.initials: EG
authors.lastname: de Jorge
authors.forename: Frédérique
authors.initials: F
authors.lastname: Brune
authors.forename: Philippe
authors.initials: P
authors.lastname: Azam
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Pickering
mesh_terms: D000818:Animals; D003167:Complement Activation; D003176:Complement C3 / Q000378:metabolism; D017242:Complement Factor H / Q000032:analysis / Q000172:deficiency* / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D050533:Glomerular Basement Membrane / Q000378:metabolism / Q000473:pathology; D015433:Glomerulonephritis, Membranous / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013997:Time Factors
chemical_list: C493495:CFH protein, human; D003176:Complement C3; D017242:Complement Factor H
references.citation: Pediatr Nephrol. 2006 Nov;21(11):1769-71
references.pmid: 16909242
references.citation: J Pediatr. 2001 Mar;138(3):412-7
references.pmid: 11241053
references.citation: Br J Haematol. 2010 Jan;148(1):37-47
references.pmid: 19821824
references.citation: J Am Soc Nephrol. 2007 Sep;18(9):2447-56
references.pmid: 17675665
references.citation: Clin Exp Immunol. 2008 Feb;151(2):210-30
references.pmid: 18190458
references.citation: Kidney Int. 1983 May;23(5):749-58
references.pmid: 6553695
references.citation: J Immunol. 1999 Oct 15;163(8):4590-6
references.pmid: 10510403
references.citation: Kidney Int. 1998 Feb;53(2):331-49
references.pmid: 9461093
references.citation: Vet Rec. 1995 Sep 2;137(10):240-4
references.pmid: 8533215
references.citation: J Immunol. 1976 Jan;116(1):1-7
references.pmid: 1245733
references.citation: J Clin Invest. 2008 Feb;118(2):608-18
references.pmid: 18202746
references.citation: Am J Pathol. 1993 Jan;142(1):179-87
references.pmid: 7678717
references.citation: Am J Nephrol. 1987;7(6):470-7
references.pmid: 3326412
references.citation: Pediatr Nephrol. 2007 Jun;22(6):874-80
references.pmid: 17295030
references.citation: Kidney Int. 2009 Jun;75(11):1230-1234
references.pmid: 18633337
references.citation: Science. 1969 Apr 25;164(3878):436-7
references.pmid: 4180576
references.citation: Vet Rec. 1997 Apr 12;140(15):392-5
references.pmid: 9141221
references.citation: Am J Kidney Dis. 2008 Apr;51(4):671-7
references.pmid: 18371543
references.citation: Am J Pathol. 1993 Nov;143(5):1356-65
references.pmid: 8238252
references.citation: Pediatr Nephrol. 2001 Jul;16(7):554-6
references.pmid: 11465803
references.citation: Am J Kidney Dis. 2005 Feb;45(2):415-21
references.pmid: 15685522
references.citation: Nat Genet. 2002 Aug;31(4):424-8
references.pmid: 12091909
references.citation: Am J Pathol. 2009 Oct;175(4):1757-67
references.pmid: 19729477
references.citation: J Clin Invest. 1995 Mar;95(3):1054-61
references.pmid: 7883953
references.citation: Kidney Int. 2006 Jul;70(1):42-50
references.pmid: 16612335
references.citation: J Am Soc Nephrol. 2005 May;16(5):1392-403
references.pmid: 15800116
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9649-54
references.pmid: 16769899
references.citation: Pediatr Nephrol. 1998 Oct;12(8):619-24
references.pmid: 9811382
references.citation: J Am Soc Nephrol. 2005 Feb;16(2):555-63
references.pmid: 15590760
references.citation: J Exp Med. 1992 Apr 1;175(4):939-50
references.pmid: 1532415
references.citation: Mol Immunol. 2009 Jun;46(10):1942-50
references.pmid: 19411110
references.citation: J Am Soc Nephrol. 2007 Apr;18(4):1157-66
references.pmid: 17344423