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Background and Aims Fabry nephropathy may progress to kidney failure despite enzyme replacement therapy (ERT) when the treatment is initiated at a relatively late stage of the disease. This study evaluates long term effects of agalsidase in serial kidney biopsies and functional measurements in men with classical Fabry disease that commenced ERT at a young age. Method Six male Fabry patients with a median age of 20 years (range 7-30 years) at start of ERT were monitored over a median time of 15 years (range 14.5-17.0 years). The patients were treated with an agalsidase dose of 1.0 mg/kg/every other weak (eow) for 8.3 years (range 5-12 years) and with an agalsidase dose of 0.2-0.5 mg/kg/eow for 7.6 years (range 3-10 years). Kidney biopsies were evaluated with the scoring system of the International Study Group of Fabry Nephropathy (ISGFN) using both plastic embedded and paraffin embedded tissue with scoring of podocyte globotriaocylceramide (Gb3) in semithin toluidine blue sections (maximum score 4.0) and scoring of vacuolization in PAS-sections (maximum score 3.0). ISGFN composite score consists of both tissue scores giving a maximum score of 7.0. Renal function was evaluated with measurement of glomerular filtration rate (GFR) with iohexol clearance (mGFR) and urinary albumin creatinine ratio (uACR). Values are given in median (range). Results Kidney biopsies at baseline contained 24 (13-42) evaluable glomeruli and had an ISGFN composite score of 7.0 (6.9-7.0). After 15 years the ISGFN composite score had decreased to 0.56 (0-4.29), scored in 24 (9-52) evaluable glomeruli. At baseline mGFR was 106 (86-113) ml/min/1.73 m2 and after 15 years mGFR decreased to 97 (73-134) ml/min/1.73 m2. uACR was 5.6 (0.1-13.6) mg/mmol at baseline and had after 15 years increased to 10.0 (1.0-107) mg/mmol. The youngest patient had significant proteinuria with uACR 107 mg/mmol due to a chronic C3-glomerulonephritis superimposed on Fabry disease. Median uACR without this patient was at 15 years 5.8 (1.0-17.7) mg/mmol. The two youngest patients had no Gb3 visible (ISGFN composite score of 0) in their last biopsy and mGFR was normal in both. In all patients the reduction of podocyte-Gb3 was higher on an agalsidase dose of 1 mg/kg/eow; change composite score -4.66 (-7.9 to -1.8), compared to on an agalsidase dose of 0.2-0.5 mg/kg/eow; change composite score -0.15 (-5.1 to + 1.0). Conclusion Initiation of ERT at a relatively young age may clear the long living kidney cells of Gb3 and protect the kidneys from significant functional loss over a very long time period. The reduction of Gb3 in podocytes is higher on high dose compared to low dose of agalsidase.

MO127CLEARED PODOCYTES AND NORMAL KIDNEY FUNCTION IN CLASSICAL FABRY MALES 15 YEARS AFTER START OF ENZYME REPLACEMENT THERAPY AT YOUNG AGE*