title: Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis.
abstract: Mutations in the fibrinogen A alpha-chain gene are the most common cause of hereditary renal amyloidosis in the United Kingdom. Previous reports of fibrinogen A alpha-chain amyloidosis have been in isolated kindreds, usually in the context of a novel amyloidogenic mutation. Here, we describe 71 patients with fibrinogen amyloidosis, who were prospectively studied at the UK National Amyloidosis Centre. Median age at presentation was 58 yr, and renal involvement led to diagnosis in all cases. Even after a median follow-up of 4 yr, clinically significant extra-renal disease was rare. Renal histology was characteristic: striking glomerular enlargement with almost complete obliteration of the normal architecture by amyloid deposition and little or no vascular or interstitial amyloid. We discovered four amyloidogenic mutations in fibrinogen (P552H, E540V, T538K, and T525fs). A family history of renal disease was frequently absent. Median time from presentation to ESRD was 4.6 yr, and the estimated median patient survival from presentation was 15.2 yr. Among 44 patients who reached ESRD, median survival was 9.3 yr. Twelve renal transplants survived for a median of 6.0 (0-12.2) yr. Seven grafts had failed after median follow up from transplantation of 5.8 yr, including three from recurrent amyloid after 5.8, 6.0, and 7.4 yr; three grafts failed immediately for surgical reasons and one failed from transplant glomerulopathy after 5.8 yr with no histological evidence of amyloid. At censor, the longest surviving graft was 12.2 yr. In summary, fibrinogen amyloidosis is predominantly a renal disease characterized by variable penetrance, distinctive histological appearance, proteinuria, and progressive renal impairment. Survival is markedly better than observed with systemic AL amyloidosis, and outcomes with renal replacement therapy are comparable to those for age-matched individuals with nondiabetic renal disease.
authors.affiliation: National Amyloidosis Centre, CAAPP, Department of Medicine, Royal Free Campus, University College London, Rowland Hill Street, London NW3 2PF, United Kingdom. j.gillmore@medsch.ucl.ac.uk
authors.forename: Julian D
authors.initials: JD
authors.lastname: Gillmore
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Lachmann
authors.forename: Dorota
authors.initials: D
authors.lastname: Rowczenio
authors.forename: Janet A
authors.initials: JA
authors.lastname: Gilbertson
authors.forename: Cai-Hong
authors.initials: CH
authors.lastname: Zeng
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Liu
authors.forename: Lei-Shi
authors.initials: LS
authors.lastname: Li
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Wechalekar
authors.forename: Philip N
authors.initials: PN
authors.lastname: Hawkins
mesh_terms: D000368:Aged; D000682:Amyloid / Q000235:genetics / Q000502:physiology; D000686:Amyloidosis / Q000175:diagnosis* / Q000401:mortality* / Q000503:physiopathology* / Q000628:therapy; D005192:Family Health; D005260:Female; D005340:Fibrinogen / Q000737:chemistry*; D006801:Humans; D016030:Kidney Transplantation / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D011877:Radionuclide Imaging / Q000379:methods; D017582:Renal Replacement Therapy / Q000379:methods; D013997:Time Factors; D016896:Treatment Outcome; D051598:Whole Body Imaging
chemical_list: D000682:Amyloid; D005340:Fibrinogen