Markers of nephropathy in young Fabry disease patients; role of kidney biopsies and functional measurements
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Backgound: Fabry disease is an X-linked disease affecting glycosphingolipid metabolism due to deficiency of the lysosomal enzyme α-galactosidase. The natural course of the disease is related to progressive accumulation of globotriaocylceramide (GL3) in various cell types and causes premature death from stroke, renal failure or cardiac disease. Modern therapies in many common kidney diseases, as well as in a rapidly increasing number of rare diseases, include potentially toxic and expensive drug interventions. As a consequence, it becomes important to use accurate methods for investigation of kidney disease.
Aims: The aims of this thesis were to evaluate early Fabry nephropathy by means of morphologic and exact functional methods in children and young adults and to validate the safety of kidney biopsies in general. Materials and methods: Renal biopsies from thirteen young patients with Fabry disease (mean age 17.3 ± 7.5, range 7-33 years) were examined before and after longterm (5 years) enzyme replacement therapy (ERT). Comparisons of different formulas for estimation of GFR (eGFR) and measured GFR (mGFR) were performed in 42 children with Fabry disease (mean age 12.3 ± 3.6, range 2-17 years). Safety evaluation of kidney biopsies was done in 715 paediatric (mean age 12.0 ± 4.9, range 0.04-17.9 years) and 8573 adult (mean age 50.6 ± 17.7, range 18.0-94.4) cases registered from 1988 to 2010 in The Norwegian Kidney Biopsy Registry.
Results: The baseline biopsies of Fabry disease patients showed disease specific potentially progressive morphologic changes in glomerular, tubulointerstitial and vascular compartments. In the follow-up biopsies complete clearance of glomerular endothelial and mesangial GL3 deposits was found in all patients and linear regression analysis showed a significant correlation between podocyte GL3-clearance and cumulative agalsidase dose (r=0.804, p=0.002). Simultaneous eGFR and mGFR analysis showed that the widely used original Schwartz formula overestimated mGFR by an average of 50.6 ml/min/1.73 m2 in our cohort with normal mGFR. Nationwide renal biopsy registry data showed that major complications after kidney biopsy were rare both in children and adults (blood transfusion 0.9 % and surgery/angiographic embolization 0.2 %), the most important risk factors for major complications were lower GFR and smaller centre size.
Conclusions and consequences: Long-term ERT clears glomerular endothelial and mesangial GL3 deposits across all dosing regimens of agalsidase. The reduction of Fabry disease specific damage in podocytes is dose-dependent, suggesting that podocyte damage may be a promising biomarker in Fabry nephropathy. Kidney biopsy is a low risk procedure and we recommend a baseline biopsy in the assessment of early renal damage in Fabry disease. A follow-up biopsy after 5 years ERT is valuable in the evaluation of progression and reversibility of kidney damage. Several GFR formulas show low accuracy in the normal GFR-range. The new abbreviated Schwartz formula (2009) has the better performance and is recommended in the routine follow-up of children with Fabry disease. Additional mGFR is recommended when exact measurements are needed; e.g. when ERT is initiated.