Fabry disease: when to suspect it and how to treat it

Transcription

1 Fabry disease: when to suspect it and how to treat it Catalina Martín Cleary Alberto Ortiz Arduán, MD, PhD IIS-Fundacion Jimenez Diaz, UAM IRSIN, REDINREN Madrid, Spain

2 Conflict of interest Consultant: Sanofi Genzyme Speaker fees: Sanofi Genzyme, Shire, Amicus

3 F BR

4 F BR _Lt._William_Marks%2C_Executive_Officer%2C_USS_Constitution%2C_talks_about_a_photo_of_the_206-year-old_warship.jpg

5 I have never seen a Fabry patient in my life! r u sure? 0.2% to 1.2% of ESRD patients have Fabry 20 to 100 x higher than in dialysis registries! van der Tol et al. J Med Genet. 2014;51:1-9 Thadhani R et al. Kidney Int. 2002;61:249-55

6 By TUBS - Own workthis vector image includes elements that have been taken or adapted from this: Usa edcp location map.svg (by Uwe Dedering).This vector image includes elements that have been taken or adapted from this: USA Hawaii location map.svg (by NordNordWest).This vector image includes elements that have been taken or adapted from this: Canada location map.svg (by Yug)., CC BY-SA 3.0,

7 Kidney disease: biopsy 8 of 11 glomeruli completely sclerotic 2 segmental sclerosis. Electron microscopy: 1 glomerulus, few visceral epithelial cells with scattered myelin bodies 29-year-old lady Diagnosis: FSGS No surname!!! HLA-identical transplant from sister (pretransplant donor work up normal) Post-transplant increasing proteinuria Biopsy extensive myelin figures consistent with Fabry disease Diagnosis confirmed in recipient, donor and donor's son

8 What did we learn? Despite being X-linked, Fabry may cause severe nephropathy in females The diagnosis may be missed, specially in the absence of EM The key target cell is the podocyte (previously thought to be the endothelium) The consequences of knowing the etiology of CKD go beyond the patient

9 Primary FSGS Fabry Obesityrelated FSGS

10 Fabry disease Genetic deficiency of the a-galactosidase A lysosomal enzyme (GLA gene): glycolipid accumulation in lysosomes and extracellular X-linked: Males (XY) have a more severe disease But females may also be severely affected: (XX) à X X X X à X X X X Mutation-dependent severity: classical and late-onset Fabry

11 Pathogenesis of Fabry disease: 3 sequential problems Enzymatic defect Glycolipid accumulation Tissue injury Burden of disease Early: neuropathic pain, hipohydrosis, angiokeratoma, digestive Late, potentially lethal tissue injury èkidney: proteinuric chronic Problem kidney 3: disease, organ dysfunction end-stage kidney disease, normotensive (mean age: 40 years in males and females) èheart: left ventricular hypertrophy and fibrosis (late enhancement MRI), arrhythmia, heart Problem failure 2: tissue (mean injury age: 45 years in males and 54 in females) ècns: WML, TIA, stroke Problem 1: glycolipid accumulation Time Eng CM et al. J Inherit Metab Dis 2007;30:

12 3 key concepts 1. Fabry causes chronic kidney disease (CKD) 2. Fabry CKD is proteinuric 3. Fabry CKD is progressive

13 Fabry nephropathy is a progressive proteinuric kidney disease of metabolic origin RRT Mean age 40 years Treatable cause of CKD!

14 Age at first renal replacement therapy Ortiz et al. NDT 2009

15 Podocyes ket cell types

16 Bye, bye podocyte!!! (podocyte crashing against toilet)

17 Increase loss of podocytes in urine of Fabry patients Fall et al, Plos One 2016; 11(12):e

18 Podocyte loss results in glomerulosclerosis (glomerular fibrosis) Missing podocyte FSGS

19 Fabry podocytes are fuuuuull of glycolipids Am J Kidney Dis May;51(5):767-76

20 Podocyte inclusions vs age Podocyte inclusions vs proteinuria Endothelial inclusions vs age No relationship between v(inc/endo) and proteinuria Relationship between age and podocyte (Vv(Inc/PC)), and endothelial cell (Vv(Inc/Endo)) GL-3 fractional volume of inclusions per cytoplasm Segmental foot process effacement was present in all glomeruli Najafian et al. Kidney International Volume 79, Issue 6, 2 March 2011, Pages

21 Warnock, et al. Nephrol Dial Transplant Mar;27(3): , Wanner, et al. Clin J Am Soc Nephrol Dec;5(12): ? Albuminuria (proteinuria» albuminuria x 2) is a major risk factor for progression of CKD in Fabry disease Nat history data Median upcr (g/g) 0 0,5 1 1, Median egfr slope (ml/min/year)

22 Pathogenesis of Fabry disease: 3 sequential problems Enzymatic defect Glycolipid accumulation Burden of disease Problem 1: glycolipid accumulation Time Eng CM et al. J Inherit Metab Dis 2007;30:

23 What are the histological features of Fabry nephropathy? 1. Glycolipid deposits (birth) Courtesy. B Najafian, Pediatr Nephrol 2013 May;28(5):679-87

24 Pathogenesis of Fabry disease: 3 sequential problems Enzymatic defect Glycolipid accumulation Tissue injury Burden of disease a. Subclinical: foot process effacement Problem 2: tissue injury Problem 1: glycolipid accumulation Time Eng CM et al. J Inherit Metab Dis 2007;30:

25 What are the histological features of Fabry nephropathy? 1. Glycolipid deposits (birth) 2. Podocyte injury (foot process effacement in childhood) Podocyte Courtesy. B Najafian, Pediatr Nephrol 2013 May;28(5):679-87

26 Pathogenesis of Fabry disease: 3 sequential problems Enzymatic defect Glycolipid accumulation Tissue injury Burden of disease b. Clinical: Increasing albuminuria within normal range Pathological albuminuria (UACR>30 mg/g) Overt proteinuria Problem 2: tissue injury Problem 1: glycolipid accumulation a. Subclinical: foot process effacement Time Eng CM et al. J Inherit Metab Dis 2007;30:

27 Pathogenesis of Fabry disease: 3 sequential problems Enzymatic defect Glycolipid accumulation Tissue injury Burden of disease c. Progressive decrease GFR b. Clinical: Increasing albuminuria within normal range Problem 3: organ dysfunction Pathological albuminuria (UACR>30 mg/g) Overt proteinuria Problem 2: tissue injury a. Subclinical: foot process effacement Time Problem 1: glycolipid accumulation Eng CM et al. J Inherit Metab Dis 2007;30:

28 Silent structural changes: Pathologic Renal biopsy al albuminuri a Proteinuria, decreased GFR

29 Silent structural changes: Renal biopsy Pathological albuminuria UACR > 30 mg/g

30 Silent structural changes: Renal biopsy Pathological albuminuria This is the timing to prevent the volcano from emerging irreversibly Proteinuria, decreased GFR

31 When should Fabry be suspected? Family history of nephropathy or other manifestation of Fabry or Classical symptoms or complications or Unexplained CKD, especially if Proteinuric, Lack of hypertension or mild hypertension < 50 year-old (male)

32 KDIGO CKD Kidney Int CGA Classification of CKD Cause GFR Albuminuria (proteinuria)

33 When should Fabry be suspected? Family history of nephropathy or other manifestation of Fabry or Classical symptoms or complications or Unexplained CKD, especially if or Proteinuric, Lack of hypertension or mild hypertension < 50 year-old (male) renal biopsy findings: white glomeruli in biopsy cylinder, foamy cells in histology, or typical EM inclusions

34 Fabry nephropathy may be missed by an unexperienced pathologist Foamy inclusions within podocytes and tubular epithelial cells (renal biopsy, haematoxylin/eosin stain, 400x magnification) Woywodt, A. et al. Nephrol. Dial. Transplant : ;

35 Fabry podocytes are fuuuuull of glycolipids Am J Kidney Dis May;51(5):767-76

36 Take home message When should the nephrologist suspect (and screen for) Fabry disease? Unexplained CKD =

37 Take home message When should the nephrologist suspect (and screen for) Fabry disease? Unexplained CKD = Genuine unexplained Bullshit diagnosis, e.g. hypertensive nephropathy Incomplete diagnosis, e.g. FSGS Lack of renal biopsy with EM

38 Diagnosis Dried blood spot (DBS) enzyme activity Males GLA exon sequencing Screening of females with high suspicion Confirmation of males

39 Diagnosis Dried blood spot (DBS) enzyme activity Males GLA exon sequencing And additional genetic tests Screening of females with high suspicion Confirmation of males

40 Therapy: multidisciplinary approach 1. Organ protective and symptomatic therapy: antiproteinuric therapy

41 Therapy: multidisciplinary approach 1. Organ protective and symptomatic therapy 2. ERT: enzyme replacement therapy

42 Sesame Street suggests endothelial findings may not apply to podocytes 2 Endothelial deposits in placebo-controlled phase II/III RCT 2 Endothelial deposits (score) 1,5 1 0,5 * Endothelial deposits (score) 1,5 1 0,5 * 0 0 Baseline 6 mo Baseline 6 mo Agal-β 1.0 mg/kg/2 weeks Agal-α 0.2 mg/kg/2 weeks Data from Eng et al, NEJM 2001, Schiffmann et al, JAMA 2001 and FDA Figure from Ortiz et al, Med Clin 2017

43 Endothelial deposits in placebo-controlled phase II/III RCT 2 2 Endothelial deposits (score) 1,5 1 0,5 * Endothelial deposits (score) 1,5 1 0,5 * 0 0 Baseline 6 mo Baseline 6 mo Agal-β 1.0 mg/kg/2 weeks Agal-α 0.2 mg/kg/2 weeks Data from Eng et al, NEJM 2001, Schiffmann et al, JAMA 2001 and FDA Figure from Ortiz et al, Med Clin 2017 BUT! Endothelial findings may not apply to podocytes

44 The Sesame Street issues: In and out In Out

45 The Sesame Street issues: sharing cookies Time Endothelial cell

46 Podocyte If you don`t share your cookies, you get to keep all of them! Time 1 y 2 y 3 y

47 The Sesame Street prediction Podocytes harder to clear than endothelial cells

48 ERT and GL-3 clearance from podocytes J Am Soc Nephrol. 2013;24: years of ERT with agalsidase alfa or agalsidase beta in 12 consecutive patients age 7-33 years (median 16 y). agalsidase alfa, 0.2 mg/kg/eow (n=5), 0.2 mg/kg/ew (n=1), 0.4 mg/kg/eow (n=1) agalsidase beta, 1.0 mg/kg/eow (n=3), 0.2 EOW (n=1) agalsidase alfa, 0.4 mg/kg/eow + then agalsidase beta, 1.0 mg/kg/eow (n=1) After a median of 65 months microalbuminuria normalized in 5 patients. Bx findings Kidney Bx Kidney Bx 5y? ww.kidneypathology. ERT (Years) Please note: Fabrazyme (agalsidase beta) is indicated in patients >/= 8 years old (EU SmPC, Jan 2017).

49 Early ERT in Fabry: Renal Bx after 5 years of ERT Correlation between cumulative dose and podocyte Gb3 clearance Endothelium cleared in all Better podocyte clearance, more reduction in albuminuria Podocyte Gb3 Dose Albuminuria Adapted from Tondel 2013, Tøndel C, J Am Soc Nephrol Jan;24(1): Fabrazyme (agalsidase beta) is indicated in patients >/= 8 years old (EU SmPC, Jan 2017)

50 What about hard outcomes? ESRD initiation of dialysis CARDIAC complications CEREBROVASCULAR events DEATH

51 Mean age 47 years (ERT) vs 44 (placebo) Mean UACR 1.3 g/g (ERT) vs 0.9 years (placebo) 1 mg/kg/2 week Events: composite clinical outcome of renal, cardiac, and cerebrovascular complications or death Per protocol population ITT population (HR 0.47, p=0.06)

52 Clinical events: Registry data

53 ERT at 1mg/kg/2 weeks with agalsidase beta was associated with a decrease in incidence of severe clinical events* AFTER 6 months of treatment Fabry registry data: 1044 patients Median age at start ERT: 40 years = late!! * severe clinical events were defined as: death, renal, cardiac event or stroke. Ortiz at al J Med Genet Jul;53(7):

54 ERT at 1mg/kg/2 weeks with agalsidase beta was associated with a decrease in incidence of severe clinical events* AFTER 6 months of treatment Fabry registry data: 1044 patients Median age at start ERT: 40 years = late!! Incidence rate within the first 6 months of ERT * severe clinical events were defined as: death, renal, cardiac event or stroke. Ortiz at al J Med Genet Jul;53(7):

55 ERT at 1 mg/kg/2 weeks with agalsidase beta was associated with a decrease in incidence of severe clinical events* AFTER 6 months of treatment Fabry registry data: 1044 patients Median age at start ERT: 40 years = late!! Lower incidence rate after 6 months of ERT * severe clinical events were defined as: death, renal, cardiac event or stroke. Ortiz at al J Med Genet Jul;53(7):

56 ERT at 1mg/kg/2 weeks with agalsidase beta was associated with a decrease in incidence of severe clinical events* AFTER 6 months of treatment Expected? Ageing? # Observed * severe clinical events were defined as: death, renal, cardiac event or stroke. Ortiz at al J Med Genet Jul;53(7): # Dr ortix s Estimates/ personal opinions based on Katherine Sims et al. Stroke. 2009;40:

57 Incidence of strokes increases with age in untreated Fabry patients and the general population 5 years Katherine Sims et al. Stroke. 2009;40: Copyright American Heart Association, Inc. All rights reserved.

58 Incidence rates of severe clinical events per 1000 patient years while on agalsidase beta: higher risk populations These data support the concept that there is no such thing as too late in Fabry disease Ortiz at al for the Fabry Registry, J Med Genet 2016

59 Take home message 1. Where is Fabry disease? Look for and recognize underlying FD in the ESRD population and CKD of unknown etiology Follow up with Family screening to identify children and patients early 2. How to treat? 1. Supportive antiproteinuric therapy 2. Optimal dose of enzyme replacement to halt progression Podocytes should be immortal: published data suggests ERT may clear them in dose-dependent manner Long-term agalsidase beta 1.0 mg/kg/2 weeks results in a reduction of incidence of severe clinical events (report from the largest Fabry disease Registry study)

60 Thank-you!

61 What is Lyso-Gb3? Lyso-Gb3 as a failed escape attempt

62 What is Lyso-Gb3? Gb3 globotriaosylceramide alpha-galactosidase A Lyso-Gb3 globotriaosylsphingosine Acid ceramidase Within the lysosome!!!

63 Lyso-Gb3 correlated with disease severity in a homogeneous population, all with the same mutation P<0.01 P<0.01 Older than 18 years Lio HC, et al. Clin Chim Acta Nov 15;426:114-20

64 ERT: Correlation between lyso-gb3 and cardiac hypertrophy responses Chen KH, et al. Can J Cardiol Oct;32(10):1221.e e9.

65 In a retrospective observational analysis, plasma lyso-gb3 increased in males when ERT was switched from agalsidase-b 1.0 mg/kg/eow to agalsidase-a 0.2 mg/kg/eow EOW: every other week 1.0 mg/kg/biweekly 1 year 0.2 mg/kg/biweekly Smid B. et al. Orphanet J Rare Dis 2011

66 Potential lyso-gb3 contributions to Fabry disease and therapeutic implications TGF-β1 Vit D receptor activators Sanchez-Niño MD, et al. Nephrol Dial Transplant Jun;26(6): Sanchez-Niño MD, et al. Hum Mol Genet Oct 15;24(20):

67 Lyso-Gb3 dose-dependently increases ECM expression mrna (% increase over control) Fibronectin Type-IV collagen * * * Fibronectin Type IV collagen 20 0 Control Lyso- Gb3 nm Control Lyso-Gb3 100nM Tipe IV collagen and Fibronectin are accumulated in glomerular sclerosis (glomerular fibrosis) Sanchez-Niño et al, NDT 2010

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