Tips & tricks bij diagnostiek van erfelijke nieraandoeningen

Prof Dr B Bammens, dienst nefrologie UZ LeuvenProf Dr K Claes, dienst nefrologie UZ Leuven

CASUS

Autosomal Dominant Polycystic Kidney Disease

Autosomal Dominant Polycystic Kidney Disease1/400 tot 1/1000 geboortes – progressieve cystische omvorming en groei nieren

nierfalen (mediaan): 58j PKD1, 79j PKD2 - 5-7% incidentie ESRD Vlaanderen

First reports: descriptive

Fogazzi et al. Nephrol Dial Transplant 13: 1039-1040, 1998

First reports: descriptive

Anatomie pathologique du corps humain, 1829Traité des maladies des reins, 1841

First reports: descriptive

“La polykystose rénale sera peut-être un jour traitable”

F. Lejars, 1888

Genetics: a giant step forward!

PKD 1 (± 80%)

cytogenetische locatie16p13.3

Genetics: a giant step forward!

PKD 2 (± 20%)

cytogenetische locatie4q22.1

Genetics: a giant step forward!

PKD1 > polycystin 1, een receptorPKD2 > polycystin 2, een transmembranair calcium kanaal

Genetics

Genetics: a giant step forward!

PKD1 truncating vs. PKD1 non-truncating vs. PKD2

Cornec-Le Gall et al. J Am Soc Nephrol 24: 1006-1013, 2013

Cornec-Le Gall et al. J Am Soc Nephrol 24: 1006-1013, 2013

mediane leeftijd nierfalen

55j PKD1 truncating

67j PKD1 non-truncating

79j PKD2

Sometimes the story is not “typical”and/or

genetic evaluation is not straigthforward.

Casus: meisje, 6 jaar consultatie pediatrie nefrologieEchografie nav buikpijnklachtenMultipele cysten rechter nier

DD dysplastische/multi-cystische nierenPUJ stenosemaligniteitADPKD (cf. familiaal verhaal)

Casus: meisje, 6 jaar

StamboomPaternele grootmoeder

55j: borst carcinoma70j: sigmoid carcinoma

60j: geïnfecteerde levercystewaarvoor drainage

INDEX

StamboomPaternele grootmoeder

Hepatomegalie, multipele cystenNormale niergrootte, 1 (corticale) cyste

INDEX

StamboomPaternele grootvader

Normale leverMeerdere corticale niercysten

(passend bij leeftijd)Geen organomegalie

INDEX

StamboomVader

Multipele verspreide levercystenMeerdere niercysten van enkele mm tot 4.4cm

Geen organomegalie

INDEX

Genetics

INDEX

TSC1 en TSC2 eveneens negatief

Genetics: is there more than PKD1 & 2?

Paul et al. Kidney Int 85: 383-392, 2014

Genetics: there is more than PKD1 & 2

Porath et al. Am J Hum Gen 98: 1193-1207, 2016

cytogenetische locatie 11q12.3

Genetics: there is more than PKD1 & 2

Cornec-Le Gall et al. J Am Soc Nephrol 29: 13-23, 2018

StamboomZus

Enkele kleine cystjes linker nier

ND mut

mutND

mut

GANAB c.890 del exon 9

INDEX

Genetics: there is more than PKD1 & 2

Cornec-Le Gall et al. Am J Hum Gen 102: 832-844, 2018

normale niergrootte, cystische omvorming evoluerend naar schrompelnierenhistologisch interstitiële fibrose in niet-cystisch parenchymrecidiverend jicht in 1 van de families

fenotypischoverlapADTKD

cytogenetische locatie 3q27.3

Genetics: there is more than PKD1 & 2

Besse et al. J Am Soc Nephrol, 2019 https://doi.org/10.1681/ASN.2019030298

normale niergrootte, multipele niercysten in meerderheid dragerslevercysten eerder uitzonderlijkgeen notie van nierfalen

cytogenetische locatie 11q23.1

Need to go that extra mile!

Translational research in ADPKDPediatric Nephrology Department UZ LeuvenPKD Group (Lab of Pediatrics)

Lab of Ion Channel Research (KU Leuven/VIB)

Center for Human Genetics UZ LeuvenLaboratory for Genetics of Human Development

Djalila Mekahli

Rudi Vennekens

Koen Devriendt

Adult Nephrology Department UZ LeuvenNephrology & Renal Transplanation Research Group

Tips & tricks bij diagnostiek van erfelijke nieraandoeningen

Prof Dr B Bammens, dienst nefrologie UZ LeuvenProf Dr K Claes, dienst nefrologie UZ Leuven

CASUS

Some facts and figures• -25% of patients with CKD family history

• 10%-20% of patients with CKD mendelian causes

• 10% of patients with CKD “others” or “unknown”

Pediatric population

05

1015202530354045

Causes of ESRD (%)

Causes of ESRD

Pediatric population (<24 yr)

Exome sequencing in CKD Adult population

Family 1

• 1: haematuria, no proteinuria, no CKD

• 2: haematuria, proteinuria, w/wo CKD

• 3: ESRD due to focal andsegmental glomerulosclerosis

3

2

3 3

21

1

Family 1

• 1: haematuria, no proteinuria, no CKD

• 2: haematuria, proteinuria, w/wo CKD

• 3: ESRD due to focal andsegmental glomerulosclerosis

Biopsy: FSGS familial FSGS

3

2

3 3

21

1

Phenotype: new roles for old genes

• 1: haematuria, no proteinuria, no CKD• 2: haematuria, proteinuria, w/wo CKD• 3: ESRD due to focal and segmental

glomerulosclerosis

10-30% of adult onset familial FSGS (COL3A4, COL3A3 and COL3A5 mutations are found)

………

Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis; Gast C NDT 2015

3

2

3 3

21

1

Family 2• Outpatient clinic: Man, 60 y old:

o CKD 3A, bland sediment, no proteinuriao Diabetes, hypertensiono Ultrasound: 9,6 cm bilateral, no cystso Family history:

• pregnancy daughter: cysts on the kidney; follow-up OK • Diabetes • Cousin with severe learning disabilities Blood test

Family 3• ♀, 24 y old• 2008: Pyelonephritis: diagnosis of ADPKD based on

bilateral renal cortical cysts, kidneys normal size(family:negative)

• 2015: increase in cysts but echographic not typical

Blood test

Family 4• ♂, 50 y• Outpatient clinic: creat 2,5 mg/dl, 29 ml/min/1,73m²• Ultrasound: small kidneys; proteinuria 0,5 g/g• Medical history: hypertension• Family history: father transplanted at the age of 55 y, eci

Genetic testing

HNF1 beta mutation• Broad phenotype

o “MODY 5”o ADTKD, RCAD, hypoplasia, CAKUTo Deletion more severe cognitive disorders (family 1) o Hepatic disorderso Tubular disorder hypomagnesemia (2/3 families)

Expanding renal diseases phenotypes• Expansions across disease categories

o COL4A mutations (FSGS/TBMN/Alport syndrome)o HNF1 beta: no clear genotypic/fenotypic correlation

(RCAD/ CAKUT/ ADTKD)o PAX2: CAKUT/SRNS

Increase in knowledge

Van Eerde et al, Kidney International 2016

~20% ESRD before age 25-30yr: monogenic hereditary

(Vivante et al, Nat Rev Nephr 2016; Van Eerde et al, Kidney International 2016)

Consequences :reclassification

Expanding renal diseases phenotypes• Expansions across disease categories

o COL4A mutations (FSGS/TBMN/Alport syndrome)o HNF1 beta: no clear genotypic/fenotypic correlation

(RCAD/ CAKUT/ ADTKD)o PAX2: CAKUT/SRNS

• Expansions within disease categorieso WT1: mutation type and location within gene

affects risk of wilms tumour and SRNSo Type of mutation severity of the disease

• Expansions within phenotypeso LMX1B: NPS,FSGS

• Leading cause of pediatricnephropathy

• In isolation or part of a syndrome

• First choice: chromosomalmicroarray/especially in syndromal form

• diagnostic yield increase in patients with parenchymaldefects

CAKUT

Risk variants: APOL 1• APOL1 (G1/G2) risk variants:

• Sub Saharan Africans

• “hypertensive” nephropathy/ non-diabetic CKD (FSGS OR 17, HIVAN OR 29-89, sickle cell nephropathy)

• Renal biopsy: FSGS and solidified glomerulosclerosis

• Renal donor: two APOL1 risk variants: higher risk of graft failure

Freedman et al: APOL-1 associated nephropathy: a keycontributor to racial disparities in CKD AJKD 2018

Therapeutic consequences• Reclassification• Treatment

o Avoidance of immunosuppressive regimens for SRNSo COQ2, COQ6, ADCK4 Coenzyme Q10o TRPC6 mutation CNI

• Management of renal transplantationo Avoidance of intense immunosuppressive regimens in SRNSo aHUS/FSGS recurrence risko AGXT mutations (Primary hyperoxaluria type 1)o Donor screening (penetrance, eg TRPC6 mutation)

• Extrarenal manifestationso HNF1 beta deletion/mutationo JAG1 mutationso Syndromal mutations

• Confirmation of diagnosis in other family members

• Presymptomatic or predictive testing

• Preimplantation genetic testing

• Carrier testing (AR/X-linked)

Therapeutic consequences

Yield in proteinuria (n=167) dd 2018

Broad inclusion…

Yield in proteinuria (n=167)

Negative92

Positive42 11

24

413211

UV33

Proteinurie (cl3 = UV)COL4A3 +INF2 +COL4A5 +COL4A4CLCN5 +ACTN4TRPC6PLCE1ANLN

Reclassification UV class IV

Nefrogeneticaraadpleging @uzleuven

Welke patiënten?

Bespreken resultaten zo geen twijfel over fenotype

Evaluatie voor start geneticascreening zo geen eenduidig fenotype

Predictieve testing

Prenatale/pre-implantatie genetische diagnostiek

Nefrogeneticaraadpleging

• Familiale anamnese

• Psychologische impact

• Kinderen?

• PGT?

• Legaal?

• Sociaal?

• Toevallige bevindingen?

From: Comparison of the Complexity of Patients Seen by Different Medical Subspecialists in a Universal Health Care SystemJAMA Netw Open. 2018;1(7):e184852. doi:10.1001/jamanetworkopen.2018.4852

Conclusions• 10% of adult and 70% of pediatric ESRD caused by inherited

kidney disease• An aid in the ‘diagnostic’ odyssey• Insight in pathogenesis, guide clinical management• Indicated: early onset ESKD and/or other clinical features

consistent with inherited kidney disease• Data sharing !!!!!!• Need for guidelines (clinical, ethical, social) and more research

ClinicalgeneticistsMedical experts

Moleculardiagnostics Genomics

Core

Extraction facilities

Acknowledgements

Dr A CorveleynE Vanhoof

Prof Dr K Devriendt

De collega’s