P199
REPORT AND RECOMMENDATIONS FROM THE 1ST INTERNATIONAL WORKSHOP ON THE
HEREDITARY AMYLOIDOSES AND VIITH INTERNATIONAL SYMPOSIUM ON FAMILIAL
AMYLOIDOSIS
Stangou, A¹Lobato, L², Zeldenrust, S³, Portmann, B¹, Linke, R4, Otto, G5, Wilczek, H6
Azoulay, D7, Picken, M8, O’Grady, J¹, Ericzon, B-G6, Heaton, N¹, Hendry, B9, Benson, M10
¹Institute of Liver Studies and Amyloidosis Treatment Centre, Kings College Hospital,
London, ²S Nefrologia, Hospital Geral de Santo António, Porto, Portugal, ³Division of
Hematology, Mayo Clinic, Rochester MN, USA, 4Reference Centre for Amyloid Diseases,
Martinsried, Germany, 5Department of Transplantation Surgery, Mainz University,
Germany, 6Division of Transplantation Surgery, CLINTEC, Karolinska University
Hospital Huddinge, Sweden, 7Centre Hepatobiliaire, Hopital Paul Brousse 94800, Villejuif,
France, 8Loyola University Medical Centre, Department of Pathology, Chicago, USA,
9
Renal Medicine, King’s College, London, 10Pathology and Laboratory Medicine, Indiana
University School of Medicine, Indianapolis, USA
Variants in the fibrinogen Aα-chain, apolipoprotein AI, apolipoprotein AII, lysozyme and gelsolin cause autosomal
dominant systemic amyloidoses, which share in common the manifestation of amyloid nephropathy in middle age and
are collectively known as ‘non-neuropathic hereditary renal amyloidoses’. The 1st International Workshop on
Hereditary Amyloidosis focused on the phenotypic description, natural course and treatment options for fibrinogen A
α-chain and apolipoprotein AI amyloidosis, the two leading causes of hereditary renal amyloid in Europe and the
USA. We present our report and recommendations.
Fibrinogen Aα-chain amyloidosis (AFib): Six mutations within the C-terminus of the fibrinogen alpha-chain gene
have been identified, all associated with renal amyloidosis and nephrotic syndrome. The most frequent is substitution
of valine for glutamic acid at position 526 (E526V). Fibrinogen is produced by the liver and outcomes of isolated
renal transplantation are poor due to rapid amyloid recurrence in the graft (10-year kidney graft survival 6%). Recent
studies on AFib disease phenotype reported autonomic neuropathy and systemic extra-renal amyloidosis including
spleen, heart, gut and coronary/cardiovascular disease including splanchnic and peripheral vessels in association with
fibrinogen amyloid deposition in the vascular walls and atheromatous plaques. High incidence of cardiovascular
disease was observed in non-nephropathic carriers. These findings have implications for the counseling of carriers and
patients, as well as, treatment. Combined liver and kidney transplant (LKT) for cases of end stage renal failure is
curative, but side-effects of renal replacement therapy (RRT) and advanced amyloid disease pose significant transplant
risks. LKT before initiating renal replacement, or possibly preemptive isolated liver transplant (LT) at early stages of
amyloid nephropathy (GFR greater than 50-60 mls/min), are preferable options. High risk or older patients who are
excluded from LT or LKT can be offered kidney grafts as best form of RRT.
Apolipoprotein AI amyloidosis (AApoAI): 14 mutations have been identified, associated with renal amyloidosis.
Mutations in the amino terminal portion of molecule (26-75) are associated with renal and hepatic amyloid, and
mutations in the carboxy terminal portion of molecule (98-178) with heart, larynx and skin amyloid. Autonomic
neuropathy may be a feature. 50% of ApoAI is produced by the liver, but disease course is slow, and long term
outcomes of isolated kidney or combined heart/ kidney transplant are satisfactory. The addition of liver transplant
(LT) to kidney graft in cases of liver and kidney failure has been associated with amyloid regression, and may be
curative. However, given the slow progression of the disease without LT, the indication for LT in AApoAI is mainly
reserved for amyloid hepatic failure rather than the systemic beneficial effect. Should LT be indicated, timing and
decisions for LT or LKT should be determined by the course of liver amyloid which takes priority over the renal
course.
Fibrinogen A α-chain and Apolipoprotein AI amyloidoses are neither non-neuropathic nor solely nephropathic, but
systemic diseases with diverse phenotype and multi-visceral, vascular, cardiac amyloid deposition and neurological
involvement. The phenotypic characterization of these systemic diseases, potential risks, and the available treatment
options should be taken into account at diagnosis, counseling of carriers and patients, follow up, and clinical
management. Upon recommendation from the 1st International Workshop panel, the familial amyloidosis world
transplant registry (FAPWTR, fapwtr@fapwtr.org) has been expanded to include the Hereditary Amyloidoses, and
offers interactive support and advice. We strongly encourage reporting to the world registry all transplant procedures
performed for these new indications, for centralised international data collection, audit, and meaningful analysis of
long-term outcomes.