Prag. Polycystic kidney disease: ARPKD & ADPKD. Max Christoph Liebau

Transcription

1 Prag Polycystic kidney disease: ARPKD & ADPKD Max Christoph Liebau Department of Pediatrics and Center for Molecular Medicine, University Hospital of Cologne Glasgow, 06th of September 2017

2 Cystic kidney diseases What are we talking about?

3 Cystic kidney diseases What are we talking about? A cyst is a fluid filled cavity lined with epithelium.

4 Kidney cyst Cystic kidney

5 Cystic kidney diseases What are we talking about? Genetic cystic kidney diseases are considered to be ciliopathies and as such are systemic disorders. Cysts are bilateral.

6 In children with a cyst, always consider a cystic kidney disease as a differential diagnosis.

7 Polycystic kidney disease Liebau & Serra Pediatr Nephrol, 2013

8 As frequently seen in medicine, the recessive form of the disease is less common but more severe. While ADPKD usually does not show any clinical symptoms perceived by the patient until well into adulthood, ARPKD is mainly a pediatric disorder.

9 ARPKD 1:20.000

10 ARPKD 1: One main gene PKHD1 encoding the ciliary protein Fibrocystin Igarashi and Somlo, JASN, 2002

11 ARPKD 1: One main gene PKHD1 encoding the ciliary protein Fibrocystin Massively enlarged kidneys Liebau and Serra, Ped Neph, 2013

12 ARPKD 1: One main gene PKHD1 encoding the ciliary protein Fibrocystin Massively enlarged kidneys Obligatory hepatic involvement CHF Ebner and Liebau, Der Nephologe 2014

13 The hepatic and the renal phenotype may differ widely in ARPKD.

14 The hepatic and the renal phenotype may differ widely in ARPKD. ARPKD is one of the two main indications for pediatric CLKTx.

15 The hepatic and the renal phenotype may differ widely in ARPKD. ARPKD is one of the two main indications for pediatric CLKTx. In a patient with ARPKD and fever, always consider cholangitis as a differential diagnosis.

16 ARPKD 1: One main gene PKHD1 encoding the ciliary protein Fibrocystin Massively enlarged kidneys Obligatory hepatic involvement CHF Pulmonary hypoplasia Ebner and Liebau, Der Nephologe 2014

17 ARPKD 1: One main gene PKHD1 encoding the ciliary protein Fibrocystin Massively enlarged kidneys Obligatory hepatic involvement CHF Pulmonary hypoplasia Hypertension, Hyponatremia Ebner and Liebau, Der Nephologe 2014

18 ARPKD 1: One main gene PKHD1 encodes Fibrocystin Massively enlarged kidneys Obligatory hepatic involvement - CHF Pulmonary hypoplasia Hypertension, Hyponatremia Variable clinical courses,

19 ARPKD-like phenotype and genetic heterogeneity Lu et al. Nat Genet, 2017

20 ARPKD-like phenotype and genetic heterogeneity Guay-Woodford et al. J Peds, 2014

21 ARPKD 1: One main gene PKHD1 encodes Fibrocystin Massively enlarged kidneys Obligatory hepatic involvement - CHF Pulmonary hypoplasia Hypertension, Hyponatremia Variable clinical courses,

22 ARPKD previous work Guay-Woodford and Desmond, Pediatrics 2003 Bergmann et al., Kidney Int 2006

23 ARPKD 1: One main gene PKHD1 encodes Fibrocystin Massively enlarged kidneys Obligatory hepatic involvement - CHF Pulmonary hypoplasia Hypertension, Hyponatremia Variable clinical courses, no targeted therapy,

24 ARPKD 1: One main gene PKHD1 encodes Fibrocystin Massively enlarged kidneys Obligatory hepatic involvement - CHF Pulmonary hypoplasia Hypertension, Hyponatremia Variable clinical courses, no targeted therapy, no established primary endpoint for clinical trials.

25 ARPKD - therapy Clinical consensus guidelines meeting in Washington in 2013 Guay-Woodford et al., J Peds 2014

26 ARPKD - therapy Clinical consensus guidelines meeting in Washington in 2013 Symptomatic therapy

27 ARPKD - therapy Clinical consensus guidelines meeting in Washington in 2013 Symptomatic therapy Neonatal Evidence for benefit of Nephrectomy is weak.

28 ARPKD - therapy Clinical consensus guidelines meeting in Washington in 2013 Symptomatic therapy Neonatal Renal Evidence for benefit of Nephrectomy is weak. Blood pressure control ACE-Inhibition Hyponatremia

29 ARPKD - therapy Clinical consensus guidelines meeting in Washington in 2013 Symptomatic therapy Neonatal Renal Hepatic Evidence for benefit of Nephrectomy is weak. Blood pressure control ACE-Inhibition Hyponatremia Watch out for cholangitis especially after KTx Watch out for portal hypertension in childhood

30 ARPKD - therapy Clinical consensus guidelines meeting in Washington in 2013 Symptomatic therapy Neonatal Renal Hepatic

31 ARPKD - therapy Clinical consensus guidelines meeting in Washington in 2013 Symptomatic therapy Neonatal Renal Hepatic more evidence needed

32 ARPKD - therapy Clinical consensus guidelines meeting in Washington in 2013 Symptomatic therapy Neonatal Renal Hepatic more evidence needed

33 ARegPKD - Aim: establish a deeply phenotyped cohort with evaluation of longterm clinical courses and current treatment approaches to lay the foundation for the potential identification of clinical and biochemical risk markers, markers of progression etc.

34 ARegPKD - Aim: establish a deeply phenotyped cohort with evaluation of longterm clinical courses and current treatment approaches to lay the foundation for the potential identification of clinical and biochemical risk markers, markers of progression etc. - Supported by the GPN, the ESPN, the ESCAPE network and the German PKD foundation, close collaboration with initiatives in the USA and the UK.

35 Ebner et al., BMC Nephrology, 2015

36 ARegPKD 94 centers in 23 countries Ebner et al., Frontiers in Pediatrics, 2017

37 Ebner et al., Frontiers in Pediatrics, 2017

38 Ebner et al., Frontiers in Pediatrics, 2017

39 Ebner et al., Frontiers in Pediatrics, 2017

40

41 ADPKD 1:500-1:1000

42 ADPKD 1:500-1:1000 Three genes, PKD1, PKD2, GANAB Igarashi and Somlo, JASN, 2002

43 ADPKD 1:500-1:1000 Three genes, PKD1, PKD2, GANAB Bilateral cystic kidneys Liebau and Serra, Ped Neph, 2013

44 Kidney cyst Cystic kidney

45 Kidney cyst or cystic kidney? Ravine criteria for at-risk individuals Pei et al., JASN, 2009

46 Kidney cyst or cystic kidney? Ravine criteria for at-risk individuals Three cysts (unilateral or bilateral) are sufficient to diagnose ADPKD in at-risk individuals aged yrs. Pei et al., JASN, 2009

47 Kidney cyst or cystic kidney? Ravine criteria for at-risk individuals Three cysts (unilateral or bilateral) are sufficient to diagnose ADPKD in at-risk individuals aged yrs. The presence of two cysts in each kidney can be regarded as sufficient for diagnosis of at-risk individuals aged 40 to 59 yrs. Pei et al., JASN, 2009

48 Kidney cyst or cystic kidney? Ravine criteria for at-risk individuals Three cysts (unilateral or bilateral) are sufficient to diagnose ADPKD in at-risk individuals aged yrs. The presence of two cysts in each kidney can be regarded as sufficient for diagnosis of at-risk individuals aged 40 to 59 yrs. For at-risk individuals aged 60 yr, in whom renal cysts are numerous in both PKD1 and PKD2 and among whom simple cysts are frequently found, the stringent criterion of four or more cysts in each kidney is required for diagnosis. Pei et al., JASN, 2009

49 Kidney cyst or cystic kidney? Ravine criteria for at-risk individuals Three cysts (unilateral or bilateral) are sufficient to diagnose ADPKD in at-risk individuals aged yrs. The presence of two cysts in each kidney can be regarded as sufficient for diagnosis of at-risk individuals aged 40 to 59 yrs. For at-risk individuals aged 60 yr, in whom renal cysts are numerous in both PKD1 and PKD2 and among whom simple cysts are frequently found, the stringent criterion of four or more cysts in each kidney is required for diagnosis. A normal ultrasound in childhood does not exclude ADPKD. Pei et al., JASN, 2009

50 ADPKD 1:500-1:1000 Three genes, PKD1, PKD2, GANAB Bilateral cystic kidneys Hepatic cysts

51 ADPKD 1:500-1:1000 Three genes, PKD1, PKD2, GANAB Bilateral cystic kidneys Hepatic cysts Pain

52 ADPKD 1:500-1:1000 Three genes, PKD1, PKD2, GANAB Bilateral cystic kidneys Hepatic cysts Pain..

53 ADPKD 1:500-1:1000 Three genes, PKD1, PKD2, GANAB Bilateral cystic kidneys Hepatic cysts Pain.. Variable courses

54 ARPKD-ADPKD overlap

55 ARPKD-ADPKD overlap - Some ARPKD patients present late - Some ADPKD patients present early

56 ARPKD-ADPKD overlap Bergmann et al., JASN 2011

57 ADPKD 1:500-1:1000 Three genes, PKD1, PKD2, GANAB Bilateral cystic kidneys Hepatic cysts Pain.. Multiple clinical studies

58 ADPKD Renal survival

59 MRI changes in childhood 13 years 17 years

60 ADPKD CRISP data Grantham et al., NEJM 2006

61 ADPKD CRISP data: Big is bad! Grantham et al., NEJM 2006

62 Genotype-Phenotype correlation Hwang et al., JASN, 2016

63 ADPKD Therapy

64 ADPKD-associated signaling Liebau and Bergmann, 2016 In Schaefer/Geary Pediatric Kidney Disease 2nd edition

65 ADPKD Tolvaptan Torres et al., NEJM 2012

66 Tolvaptan in children? Ped Neph, 2017

67 ADPKD HALT PKD Activation of an intrarenal RAS has been suggested.

68 ADPKD HALT PKD Activation of an intrarenal RAS has been suggested. Kidneys of hypertensive patients grow faster than kidneys of normotensive patients.

69 Halt-PKD-Studies NEJM 2014

70 ADPKD hypertension in children ABDM required around 30% non-dippers (ADPKiD)

71 ADPKD hypertension in children ABDM required around 30% non-dippers (ADPKiD) Kidneys of hypertensive children with ADPKD are bigger than kidneys of normotensive ADPKD children. Cadnapaphornchai et al., CJASN 2009

72 Screen for ADPKD in children?

73 Screen for ADPKD in children? - Ethical considerations - Early therapy? - Does diagnosis make a difference for patient treatment? What is the benefit for a specific patient?

74 ADPedKD

75 ADPedKD - A web-based registry for pediatric ADPKD - Joint project with Djalila Mekahli, Stehanie De Rechter, Leuven - Aim: generate observational evidence for pediatric risk score - Assess effects of early treatment

76 ADPedKD - A web-based registry for pediatric ADPKD - Joint project with Djalila Mekahli, Stehanie De Rechter, Leuven - Aim: generate observational evidence for pediatric risk score - Assess effects of early treatment - Supported by ESPN, ERA-EDTA, PKD international - Positive decision of Ethics committee - First patients included -

77 Summary ARPKD and ADPKD are the main forms of PKD.

78 Summary ARPKD and ADPKD are the main forms of PKD. ADPKD is classically presenting in adulthood, while ARPKD usually becomes clinically relevant in childhood and adolescence.

79 Summary ARPKD and ADPKD are the main forms of PKD. ADPKD is classically presenting in adulthood, while ARPKD usually becomes clinically relevant in childhood and adolescence. There are currently no established causative treatment options for pediatric cystic kidney diseases. Treatment remains symptomatic. Blood pressure control is crucial.

80 Summary ARPKD and ADPKD are the main forms of PKD. ADPKD is classically presenting in adulthood, while ARPKD usually becomes clinically relevant in childhood and adolescence. There are currently no established causative treatment options for pediatric cystic kidney diseases. Treatment remains symptomatic. Blood pressure control is crucial. For ARPKD expert opinion recommendations have been established.

81 Summary ARPKD and ADPKD are the main forms of PKD. ADPKD is classically presenting in adulthood, while ARPKD usually becomes clinically relevant in childhood and adolescence. There are currently no established causative treatment options for pediatric cystic kidney diseases. Treatment remains symptomatic. Blood pressure control is crucial. For ARPKD expert opinion recommendations have been established. For ADPKD various trials have been performed and multiple clinical studies are ongoing. There are first pediatric studies.

82 Summary ARPKD and ADPKD are the main forms of PKD. ADPKD is classically presenting in adulthood, while ARPKD usually becomes clinically relevant in childhood and adolescence. There are currently no established causative treatment options for pediatric cystic kidney diseases. Treatment remains symptomatic. Blood pressure control is crucial. For ARPKD expert opinion recommendations have been established. For ADPKD various trials have been performed and multiple clinical studies are ongoing. There are first pediatric studies. Both ARPKD and ADPKD are systemic disorders. Patientns benefit from interdisciplinary treatment.

83 Thank you AG Liebau Dr. Claudia Dafinger Dr. Kathrin Burgmaier Sophie Haumann Abdelaziz Akarkach Asem Al-Hamed Amrei Mandel Nora Liekenbroeck Joy Brandt Giulia Berger Büsra Yildirim Bodo Beck Thomas Benzing Carsten Bergmann Reinhard Büttner Jörg Dötsch Lisa Guay-Woodford Rachel Giles Gero von Gersdorff Heike Göbel Dieter Haffner Friedhelm Hildebrandt Thomas Illig Martin Konrad Kevin Kunzmann Djalila Mekahli Dominik Müller Roman Müller Heymut Omran H. Christian Reinhardt Markus Rinschen Moin A. Saleem Anja Sander Franz Schaefer Bernhard Schermer Lutz Weber Steffi Weber Thomas Weimbs Klaus Zerres and many more GPN and ESCAPE centers