Podocytopathies and Inherited Nephrotic Syndrome

Transcription

1 Podocytopathies and Inherited Nephrotic Syndrome Franz Schaefer University of Heidelberg, Germany

2 Idiopathic Nephrotic Syndrome Most common chronic kidney disease in childhood: prevalence 1/7,000 among Caucasians, 1/1,200 among Asians Good long-term prognosis of steroid sensitive forms [RUBRIKENN AME] [PROZENTSA TZ] [RUBRIKENN AME] [PROZENTSA TZ] [RUBRIKENN AME] [PROZENTSA TZ] 40% frequently relapsing/ steroid dependent phenotypes FRNS/SDNS: Significant 2 morbidity from steroid toxicity [RUBRIKENN AME] [PROZENTSA TZ] [RUBRIKENN AME] [PROZENTSA TZ]

3 Idiopathic Nephrotic Syndrome Steroid-sensitive NS Steroid-resistant NS Minimal Change GN CNI sensitivity Post-tx recurrence T-cell disorder Circulating permeability factor Structural anomalies of glomerular filtration barrier Focal Seg Glomerulosclerosis Diffuse mesangial sclerosis

4 Jul-09 Jan-10 Jul-10 Jan-11 Jul-11 Jan-12 Jul-12 Jan-13 Jul-13 Jan-14 Jul-14 Jan-15 Jul-15 Jan-16 Jul-16 Jan-17 Jul-17 Patients The PodoNet SRNS Registry 69 centers in 22 countries Enrolment Poland Germany 2,000 Iran Italy Turkey Serbia Chile Syria Lithuania Colombia France Georgia Portugal UAE Greece Czech Republic Lebanon Austria Hungary Sweden 1,500 1,

5 % patients without ESRD Response to Intensified Immunosuppression Predicts Renal Prognosis Full Remission Partial Remission No Remission PodoNet: 1900 children with SRNS Trautmann et al. JASN 2017 Time from diagnosis (years)

6 Next Generation Sequencing: Diagnostic Revolution in Hereditary Diseases

7 Podocyte Gene Discovery

8 NGS Podocytopathy Gene Panel Screening 8 Known Genes(n=30) AD genes: ACTN4, ANLN, INF2, TRPC6, ARHGAP24 AR genes: NPHS1, NPHS2, PLCE1, MYO1E, DGKE, CD2AP, PTPRO, CRB2, EMP2 Syndromic genes: LAMB2, LMX1B, GLA, SMARCAL1, WT1, ITGA3, PAX2, WDR73 Collagenopathy genes: COL4A3 COL4A4 COL4A5 Mitochodropathies: COQ2, COQ6, PDSS2, MT-TL1, ADCK4 Candidate Genes (n=11) APOL1, C14orf142, ITGB4, KANK2, MAGI2, MPDZ, MYH9, CD151, TTC21B, SCARB2, ARHGDIA

9 Genetic diagnosis made in 333 of 1,294 SRNS subjects (25.7%) Mutation detection rate: 41% of familial cases 36% of sporadic but consanguineous cases 19% of sporadic, non-consanguineous cases GENE N P H S 1 N P H S 2 W T 1 I N F 2 P L C E 1 T R P C 6 C D 2 A P A C T N 4 C O Q 2 C O Q 6 L A M B 2 L M X 1 B S M A R C A L 1 A D C K 4 A R H G D I A I T G A 3 M Y O 1 E M Y H 9 P T P R O C 1 4 O R F C D E M P 2 P D S S 2 S C A R B 2 A R H G A P 2 4 K A N K 2 I T G B 4 M A G I 2 M P D Z T T C 2 1 B mt - T L 1 CLASSIFICATION 1st line SRNS gene 1st line SRNS gene 1st line SRNS gene ; syndromic gene well-acknowledged causative gene well-acknowledged causative gene well-acknowledged causative gene well-acknowledged causative gene well-acknowledged causative gene syndromic gene syndromic gene syndromic gene syndromic gene syndromic gene novel gene proposed in a few recent studies novel gene proposed in a few recent studies novel gene proposed in a few recent studies novel gene proposed in a few recent studies novel gene proposed in a few recent studies novel gene proposed in a few recent studies novel gene proposed in a few recent studies novel gene proposed in a few recent studies novel gene proposed in a few recent studies novel gene proposed in a few recent studies novel gene proposed in a few recent studies candidate gene candidate gene candidate gene candidate gene candidate gene candidate gene candidate gene

10 Distribution of SRNS Subtypes n=899 Partially IS responsive 11% Fully IS responsive 18% Sporadic, multidrug resistant 32% Genetic/familia l, multidrug resistant 39% PodoNet 3/2015

11 Genetic Forms of SRNS: Age at Manifestation 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% genetic idiopathic Age (years)

12 Response to Intensified Immunosuppression by Genetic Status complete remission partial remission sporadic - not tested sporadic - no gene identified familial - no gene identified genetic % of patients

13 % patients without ESRD Prognostic Impact of Genetic Diagnosis Sporadic, CNI responsive Familial Sporadic, multidrug resistant Genetic Trautmann et al. JASN 2017 Time from diagnosis (years)

14 Genetic Findings Predict Post-Tx Recurrence Risk 1766 patients with primary SRNS 260 transplant recipients 233 with recurrence information Idiopathic n=105 (49.5%) Recurrence Yes n=37 No n=196 idiopathic genetic unknown 4 17 Genetic n=107 (50.5%) Recurrence rate 27.6% Recurrence rate 15.8 % Recurrence rate 3.7 %

15 Factors Associated with Renal Survival Cox Proportional Hazard Analysis Hazard Ratio p Age at start of disease Familial disease Causative NPHS1 mutation 4.06 < Causative NPHS2 mutation Causative WT1 mutation Histology (reference: MCN) DMS 6.95 < FSGS GGS MPGN

16 SRNS Management in the Genetic Era Ceylin, 10 months: Referred for NS since 3nd month of life Steroid resistance, failure to thrive NGS panel screening within 10 days: Homozygous mutation in NPHS2 Kidney biopsy cancelled Parents informed about ESRD perspective, but no risk of post-tx recurrence All immunosuppressants stopped Combined ACE&ARB therapy Clinically asymptomatic Gradually progressive CKD Pre-emptive kidney transplantation at age 4 years

17 Podocytopathy Genes 17 Cytoskeleton proteins ACTN4, 5 Mitochondrial proteins (CoQ10 synthase) COQ2, 8 ADCK4, 20 INF2, 16 mt-tl1, 3 COQ6, 4 MYOE1, 10 TTC21B, 4 NPHS2, 49 Slit diaphragm ITGB4, 1 LAMB2, 15 NPHS1, 40 COL4A4, 19 WT1, 37 Basement membrane proteins COL4A3, 24 COL4A5, 31 SMARCAL1, 12 LMX1B, 17 Transcription factors PLCE1, 14 TRPC6, 24 PAX2, 8 Signaling proteins

18

19

20 % patients without ESRD Renal Prognosis by Genetic Disorder WT1 NPHS1 NPHS2 Time from diagnosis (years)

21 Clinical Spectrum of WT1 Mutations Denys Drash Syndrome: Male-to-female sex reversal Nephrotic syndrome Diffuse mesangial sclerosis Wilms Tumor Frasier Syndrome: Male-to-female sex reversal Nephrotic syndrome Focal segmental glomerulosclerosis Gonadoblastoma Isolated steroid resistant nephrotic syndrome

22 Genotype-Phenotype Association for WT1 Mutation Subtypes Nephroblastoma 0% sex reversal FSGS > DMS Late renal failure Nephroblastoma 27% sex reversal DMS > FSGS Early renal failure Gonadoblastoma 67% sex reversal FSGS Early onset, slow progression, late renal failure Lipska et al. Kidney Int 2014

23 WT1: Kidney Survival by Mutation Type Lipska et al. Kidney Int 2014

24 Schimke Immuno-Osseous Dysplasia PodoNet-EURenOmics Cohort: 34 patients from 28 families 26% incidental finding by NGS screening (mutation detection rate: 0.8% among 1105 consecutively screened SRNS cases

25 Statural Growth At birth: 96% low birth weight 52% preterm At diagnosis: Short stature in all patients Mean height SDS -3.9 ± 1.2 At last follow-up (mean 4.8 y): Mean height SDS -5.4 ± 2.0 No response to GH therapy (tried in 8 pts; low IGF1 and/or GH deficiency in 5/6 pts)

26 Entire Cohort Patients diagnosed from phenotype Patients diagnosed via NGS testing N (female) 34 (20) 23 (17) 11 (3) Age at diagnosis [years] 4.4 ( ) 4.1 ( ) 5.3 ( ) Nephrotic range proteinuria 69.0% 66.6% 72.7% Age at ESKD [years] 6.6 ( ) 6.2 ( ) 8.7 ( ) Survival rate by age 10 years 58.4±5.8% 48.6±5.7% 84.6±9.9% Short stature 100% 100% 100% IUGR 96.4% 100% 87.5% Lymphocyte abnormalities 82.8% 90.5% 62.5% Recurrent and/or severe infections 58.6% 72.2% 36.4% Preterm delivery 57.1% 65.0% 37.5% Abnormal thyroid function 53.6% 52.4% 57.1% Cerebral ischemic events 35.3% 43.5% 18.2% Seizures 26.5% 34.8% 18.2% Cognitive impairment 28.1% 34.8% 9.1% Lymphoproliferative disorder 9.1% 13.6% 0 Autoimmune disorders 9.1% 8.7% 10%

27 Patient Survival Renal Survival

28 Ahmad, born 2005 First child of consanguineous Emirati parents Age 15 months: Severe nephrotic syndrome Primary steroid resistance Biopsy: FSGS 3 months cyclophosphamide: no effect 6 months ciclosporin A: no effect Multiple side effects of immunosuppressive medications Progression to end-stage kidney disease at age 2 years PD for three years Age 6 years: Living related kidney transplantation (donor: father) Successful, no relapse

29 Ahmad, born 2005 Genetic screening negative for NPHS2, NPHS1, WT1 Post-transplant course complicated by frequent upper respiratory tract infections, otitis media, impaired hearing -> tympanon tubes inserted Hearing not improved -> audiometry: sensorineural hearing loss! Parents want to have second child, interested to establish genetic diagnosis Whole exome sequencing reveals homozygous mutation in COQ6 COQ6 mutations first described in 2011 to cause SRNS and congenital deafness!

30 Coenzyme Q10 (Ubiquinone) Desbats et al. J Inherit Metab Dis 2015

31 Defects of Coenzyme Q10 Biosynthesis Sensorineural deafness, nephrotic syndrome Desbats et al. J Inherit Metab Dis 2015

32 Defects of Coenzyme Q10 Biosynthesis Isolated nephrotic syndrome Desbats et al. J Inherit Metab Dis 2015

33 ADCK4 Glomerulopathy Features at first manifestation: Median age 14 years Largely isolated renal phenotype Insidious onset: 57% sub-nephrotic proteinuria, 96% none or mild edema 46% CKD % FSGS Korkmaz et al. JASN 2016

34 Oral CoQ10 Supplementation in ADCK4 Glomerulopathy 8 children, mean treatment duration 8 (2-12) months Atmaca et al. PN 2017

35 Genetic Causes of SRNS: NGS Panel Results 35 ADCK4, 20 ITGB4, 1 LAMB2, 15 ACTN4, 5 MYOE1, 10 INF2, 16 mt-tl1, 3 COQ6, 4 COQ2, 8 TTC21B, 4 NPHS2, 49 NPHS1, 40 Hereditary mitochondriopathies: Disease cause in 2% of all, 10% of confirmed hereditary SRNS cases COL4A4, 19 WT1, 37 COL4A3, 24 LMX1B, 17 COL4A5, 31 PLCE1, 14 TRPC6, 24 SMARCAL1, 12 PAX2, 8

36 Ahmad, born 2005 COQ6 mutation discovered too late to save kidney function Oral CoQ10 still started hoping to slow hearing loss Audiometry findings stable during 3 years of treatment in vitro fertilization with pre-implantation diagnostics: -> Implantation of COQ6 wildtype embryo August 2016: birth of healthy brother!

37 PodoNet Partners Chile: M.Azocar, L. Quiroz, Santiago Colombia: L.M.Serna Higuita, Medellin Czech Republic: J.Dusek, Prague France: B. Ranchin, Lyon. J. Terzic, Strasbourg Georgia: T.Davitaia, Tbilisi Germany: J. Gellermann, Berlin., M.v.Husen, Hamburg. A.Melk, Hannover, S.Glasenapp. Rostock, A.Trautmann, F.Schaefer, Heidelberg Hungary: P.Sallay, Budapest Iran: A.Gheissari, Isfahan Italy: M.Noris, Bergamo. A. Pasini, Bologna. F.Emma, Rome M.Bodria, Genova, Sara Testa, Milano. E.Bennetti, Padova Lithuania: A. Jankauskiene, Vilnius Poland: A.Wasilewska, Bialystok. E.Gacka, Chorzow. I.Balasz-Chmielewska, Gdansk. D.Drozdz, Krakow. M.Tkaczyk, Lodz. T.Urasinski, Szczecin. A.Firszt- Adamczyk, Torun. E.Kuzma-Mroczkowska, Warsaw. A.Medynska, Wroclaw. M.Szczepanska, Zabrze Serbia: A.Peco-Antic, R.Bogdanovic, Belgrade Sweden: R.T. Krmar, Stockholm Switzerland: G.Simonetti, Berne Syria: B.Saeed, Damascus Turkey: A.Anarat, Adana. F.Ozaltin, E.Baskin, O.Sakallioglu, O.Soylemezoglu, N.Cakar, O.Erdogan, Z. Birsin Özkaya, Ankara. S.Akman, Antalya. A.Balat,Gaziantep. F.Gok, Gulhane. S.Emre, S.Caliskan, C.Candan, Istanbul, B.Sozeri, Izmir. I.Akil, P.Ertan, Manisa. O.Özkaya, Samsun, M.Kalyoncu, Trabzon