Anderson-Fabry disease is an X-linked lysosomal storage disorder, causing significant morbidity and premature death; cardiac and renal involvements are the major determinants of overall disease prognosis. Fabry cardiomyopathy is characterized by a hypertrophic phenotype, in the setting of histological cardiomyocyte hypertrophy and myocardial fibrosis; myocardial fibrosis is an irreversible event and affects the prognosis.
A progressive chronic kidney disease characterizes Fabry disease nephropathy; however it is clinically silent for a long period, because heavy storage may occur in renal cells with minimal or no changes on standard renal tests. Furthermore, accumulating evidence suggests that early enzyme replacement therapy is effective in preventing progression of both cardiomyopathy and nephropathy. Therefore, in this thesis I have studied two linked research questions in a multicenter, prospective, longitudinal (evaluation at baseline, 12 months and 24 months) and diagnostic test study:
1) Role of biomarkers related to collagen type I metabolism in the diagnosis of incipient and prognosis of Fabry cardiomyopathy, in a cohort of 60 patients with Fabry disease and 20 healthy controls, according to subgroups of increasing disease severity. I found that collagen type I synthesis is increased in Fabry disease cardiomyopathy, even in the earlier stages of the disease, and this profibrotic state has good prognostic value for and is likely to be critical to the development of overt left ventricular hypertrophy.
Moreover, inhibition of enzymes involved in collagen type I cleavage also seems crucial to myocardial collagen deposition and is related to risk of progressive diastolic dysfunction.
2) Identification of early and prognostic biomarkers of Fabry nephropathy in a cohort of 78 patients with Fabry disease and 25 healthy controls, according to subgroups of increasing disease severity. I have shown that two biomarkers of glomerular damage (urinary transferrin and collagen type IV excretion) and three biomarkers of tubular injury (urinary α1-microglobulin, N-acetyl-β-D-glucosaminidase and alanine aminopeptidase excretion) may overcome the limitations of albuminuria as a sensitive marker of early renal dysfunction; furthermore N-acetyl-β-D-glucosaminidase presented the better prognostic value in the identification of patients at risk for chronic kidney disease progression. These biomarkers may also define novel early stages of nephropathy characterized by mesangial expansion and/or tubular damage
