1. RENAL INVOLVEMENT IN FABRY DISEASE Sandro Feriozzi Nephrology and Dialysis AUSL/VT Italy

2. BIOCHIMICA & GENETICA Bishop PNAS 1988

3. GENETICA TRASMISSIONE IPOTESI DI LYON

7. 20 y.o. 24/h prot <3g eGFR: norm. BP: norm 30-35 y.o. 24/h prot <3g eGFR BP  >40 y.o. 24/prot <3g eGFR BP  NATURAL HISTORY OF FABRY NEPHROPATHY tubular defects Over the last 10 years something has been changed: Pathogenesis Prevalence Clinical picture ( consistent with) Treatment of the nephropathy Urinary biomarkers

8. PATHOGENESIS OF THE NEPHROPATHY Intracellular deposition of Gb3 podocyte endothelium tubular epithelium cellular damage segmental sclerosis ischemia tubular defects Thadhani Madrid 2002

9. PODOCYTE & Lyso Gb3 Sanchez-Nino, NDT 2011

10. PREVALENCE OF FABRY IN DIALYSIS USRDS EDTA - ERA JAPAN prevalence % 42/250.000 83/440.000 2/250 0.0167% 0.0188% 0.8% ITALY JAPAN AUSTRIA prevalence % 16/6378 6/514 4/2480 0,25% 1,2% 0,16% Spada J Inherit Metab Dis 2002 Nakao Kidney Int 2003 Kotanko JASN 2004 Thadhani, Kidney Int. 2002 Muto JASN 2000 In dialysis unit it is reasonable estimate 1 Fabry /100 pts Prevalence 1:17.000 / 1:117.000 ( UpToDate 2013 ) Maruyama (CJASN 2013) 47/1453 (3%) pts with low α- gal, but only 3 (0.2%) with LysoGb3 detectable, only 1 with mutation-causing disease

11. We will try to evaluate nephrological data from : Proteinuria Hypertension Renal function Clinical aspects During these years something has been changed : Prevalence Clinical picture (consistent with) Treatment of the nephropaty

13. ARTERIAL HYPERTENSION Ortiz, NDT 2008 The same results have been reported by Kleinert in FOS AJH 2006 Hypertension does not appear to be a major contributing factor in the progression Branton JASN 2002

14. NATURAL RENAL PROGRESSION Schiffmann,NDT 2009

15. DON ‘T FORGET THE FEMALES IN EARLY DETECTION Events precede diagnosisEvents follow diagnosis CARDIAC RENAL CEREBROVAS: CARDIAC RENAL CEREBROVAS: males females - 40 60 - 20 0 0 20 40 Years from clinical diagnosis «Although the signs of disease in women, in general occur later and with slower clinical progression compared with men, women can suffer from all the signs and symptoms of the disease» Parini & Feriozzi, Exp Opin Orphan Drugs 2013

16. PLOTS OF eGFR THROUGHOUT THE STUDY Feriozzi, CJASN 2012 LabelEstimatePr > |t| Slope (mL/min/1.73m2/year) - Female-0.70800.0502 Slope (mL/min/1.73m2/year) - Female Stage 1-1.36750.0304 Slope (mL/min/1.73m2/year) - Female Stage 2-0.26260.5298 Slope (mL/min/1.73m2/year) - Female Stage 3-0.49380.5245 Slope (mL/min/1.73m2/year) - Male-2.2334<.0001 Slope (mL/min/1.73m2/year) - Male Stage 1-2.5500<.0001 Slope (mL/min/1.73m2/year) - Male Stage 2-1.64930.0007 Slope (mL/min/1.73m2/year) - Male Stage 3-2.50110.0003

17. ANNUALLY eGFR SLOPE -ml/min/1,73m 2 -ml/min/year Without/ with hypertension Feriozzi, CJASN 2012

18. Tondel JASN 2013

20. Rombach, OJRD 2013 LONG-TERM OUTCOME OF ERT

21. Cybulla, JN 2012

22. There was no significant correlation between urine lyso-Gb3 and eGFR. Therefore, lyso-Gb3 is not a good predictive biomarker for kidney involvement. Auray-Blais, Clin Chim Acta 2010 Rombach PloOne 2012 URINARY BIOMARKERS During these years something has been changed: Prevalence Clinical picture ( consistent with) Treatment of renal signs Urinary biomarkers

23. Kistler, Plosone 2012 URINARY BIOMARKERS

24.  Proteinuria and hypertension are risk factors for the progression of renal disease and should be managed appropriately  Early detection of renal involvement should be achieved by regular measurement of GFR and proteinuria in both sexes  The role of biomarkers in diagnosis and in monitoring therapy is promising but not clear yet  Early intervention with ERT and adjunctive therapy can stabilize renal function or significantly slows down its decline Waldek & Feriozzi submitted CONCLUSIONS