Treatment with human complement factor H rapidly reverses renal complement deposition in factor H-deficient mice.
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.
Fakhouri
Fadi
F
Rheumatology Section, Imperial College, London, UK.
de Jorge
Elena Goicoechea
EG
Brune
Frédérique
F
Azam
Philippe
P
Cook
H Terence
HT
Pickering
Matthew C
MC
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
C493495:CFH protein, human; D003176:Complement C3; D017242:Complement Factor H
Pediatr Nephrol. 2006 Nov;21(11):1769-71
16909242
J Pediatr. 2001 Mar;138(3):412-7
11241053
Br J Haematol. 2010 Jan;148(1):37-47
19821824
J Am Soc Nephrol. 2007 Sep;18(9):2447-56
17675665
Clin Exp Immunol. 2008 Feb;151(2):210-30
18190458
Kidney Int. 1983 May;23(5):749-58
6553695
J Immunol. 1999 Oct 15;163(8):4590-6
10510403
Kidney Int. 1998 Feb;53(2):331-49
9461093
Vet Rec. 1995 Sep 2;137(10):240-4
8533215
J Immunol. 1976 Jan;116(1):1-7
1245733
J Clin Invest. 2008 Feb;118(2):608-18
18202746
Am J Pathol. 1993 Jan;142(1):179-87
7678717
Am J Nephrol. 1987;7(6):470-7
3326412
Pediatr Nephrol. 2007 Jun;22(6):874-80
17295030
Kidney Int. 2009 Jun;75(11):1230-1234
18633337
Science. 1969 Apr 25;164(3878):436-7
4180576
Vet Rec. 1997 Apr 12;140(15):392-5
9141221
Am J Kidney Dis. 2008 Apr;51(4):671-7
18371543
Am J Pathol. 1993 Nov;143(5):1356-65
8238252
Pediatr Nephrol. 2001 Jul;16(7):554-6
11465803
Am J Kidney Dis. 2005 Feb;45(2):415-21
15685522
Nat Genet. 2002 Aug;31(4):424-8
12091909
Am J Pathol. 2009 Oct;175(4):1757-67
19729477
J Clin Invest. 1995 Mar;95(3):1054-61
7883953
Kidney Int. 2006 Jul;70(1):42-50
16612335
J Am Soc Nephrol. 2005 May;16(5):1392-403
15800116
Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9649-54
16769899
Pediatr Nephrol. 1998 Oct;12(8):619-24
9811382
J Am Soc Nephrol. 2005 Feb;16(2):555-63
15590760
J Exp Med. 1992 Apr 1;175(4):939-50
1532415
Mol Immunol. 2009 Jun;46(10):1942-50
19411110
J Am Soc Nephrol. 2007 Apr;18(4):1157-66
17344423