O74 HEREDITARY RENAL AMYLOIDOSIS ASSOCIATED WITH MUTANT FIBRINOGEN AΑ-CHAIN: CLINICAL PRESENTATION, MOLECULAR BASIS, HISTOLOGICAL FEATURES AND OUTCOME OF RENAL REPLACEMENT THERAPY Gillmore JD, Lachmann HJ, Rowczenio D, Gilbertson JA, Wechalekar AD, Hawkins PN UCL Medical School, London INTRODUCTION: Mutations in the fibrinogen Aα-chain gene are the commonest cause of hereditary renal amyloidosis in the UK but only isolated kindreds with fibrinogen Aα-chain amyloidosis (AFib) have been reported. We report here the clinical presentation, histological features, molecular basis and outcome among 70 patients with AFib. Methods: All patients with AFib who were prospectively followed at the National Amyloidosis Centre (NAC) between 1992 and 2007 were identified from the NAC database. Histology was reviewed and genetic analysis was undertaken at the NAC. RESULTS: A renal presentation was universal. Asymptomatic splenic amyloid was detected by SAP scintigraphy in 89% patients but liver involvement was present in only one case. There was no echocardiographic evidence of cardiac amyloid or clinically significant autonomic neuropathy at presentation. Peripheral neuropathy was detected in 4 patients, although only thought to be due to amyloid in a single case. Median (range) age at presentation and diagnosis was 58 (33-83) and 59 (33-84) years respectively. A family history of renal disease was frequently absent. Renal histology revealed striking enlargement of the glomeruli by extensive amyloid deposits in all of 63 biopsied cases with little or no vascular or interstitial amyloid, a virtually pathognomonic appearance. Sixty-three patients were heterozygous for a fibrinogen mutation encoding the E526V variant; the R554L, E540V and P552 variants were present in 2, 2 and 1 patient respectively. Two novel mutations encoding the T538K and T525Tfs variants were discovered. Six patients had clonal plasma cell dyscrasias that were unrelated to their amyloidosis. Median time from presentation to ESRD was 4.6 years and median rate of GFR loss among those presenting with a GFR >20 ml/min was 9.4 ml/min/year. Median patient survival from presentation by Kaplan- Meier estimate was 15.2 years and median (range) age at death was 67 (57-76) years. Among 44 patients who had reached ESRD at the time of censor, median survival from RRT was 8.4 years. Median survival on dialysis (censored at the time of transplantation) was 9.3 years. Renal transplantation was undertaken in 10 patients including 2 grafts in one patient. By Kaplan-Meier estimate, median (range) renal allograft survival was 6.0 (0-12) years. A total of six grafts were lost, 3 due to recurrent amyloid after 5.8, 5.9 and 7.4 years respectively, 2 immediately post-operatively and 1 due to transplant glomerulopathy after 5.8 years. Median (range) follow up from transplantation among those with functioning grafts was 4.7 (0.7- 12) years. CONCLUSION: Hereditary AFib is a predominantly renal disease, characterised by variable penetrance, a distinctive renal histological appearance, proteinuria and progressive CKD. Patient survival is markedly better than in systemic AL amyloidosis and outcomes with dialysis and transplantation are comparable to those among age-matched non-diabetic nephropaths.