RENAL INVOLVEMENT IN FABRY DISEASE

Sandro Feriozzi

Nephrology and Dialysis

AUSL/VT

Italy

BIOCHIMICA & GENETICA

Bishop PNAS 1988

GENETICA

TRASMISSIONE IPOTESI DI LYON

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

PATHOGENESIS OF THE NEPHROPATHYIntracellular deposition of Gb3

podocyte endothelium tubular epithelium

cellular damage

segmental sclerosis ischemia tubular defects Thadhani Madrid 2002

PODOCYTE & Lyso Gb3

Sanchez-Nino, NDT 2011

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 AUSTRIAprevalence % 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 ptsPrevalence 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 1with mutation-causing disease

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

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

NATURAL RENAL PROGRESSION

Schiffmann,NDT 2009

DON ‘T FORGET THE FEMALES IN EARLY DETECTION

Events precede diagnosis Events follow diagnosis

CARDIAC

RENAL

CEREBROVAS:

CARDIAC

RENAL

CEREBROVAS:

malesmales

femalesfemales

- 40- 40 6060- 20- 20 00 2020 4040

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

PLOTS OF eGFR THROUGHOUT THE STUDY

Feriozzi , CJASN 2012

Label Estimate Pr > |t|Slope (mL/min/1.73m2/year) - Female -0.7080 0.0502

Slope (mL/min/1.73m2/year) - Female Stage 1 -1.3675 0.0304

Slope (mL/min/1.73m2/year) - Female Stage 2 -0.2626 0.5298

Slope (mL/min/1.73m2/year) - Female Stage 3 -0.4938 0.5245

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 -1.6493 0.0007

Slope (mL/min/1.73m2/year) - Male Stage 3 -2.5011 0.0003

ANNUALLY eGFR SLOPE

-ml/

min

/1,7

3m2

-ml/

min

/yea

r

Without/ with hypertension

Feriozzi, CJASN 2012

Tondel JASN 2013

Rombach, OJRD 2013

LONG-TERM OUTCOME OF ERT

Cybulla , JN 2012

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

Kistler , Plosone 2012

URINARY BIOMARKERS

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