1. Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease with more than one face Ihab Shaheen Consultant Paediatric Nephrologist RHSC- Glasgow

2. Learning objectives: Epidemiology Genetics Clinical feature 2 Cases Differential diagnoses Prognosis Literature To take home

3. Epidemiology: Inherited disorder – progressive enlargement of renal collecting ducts varying degrees of hepatic abnormality Rare 1:10,000 to 1:40,000 Caucasians > other ethnic groups? M = F

4. Epidemiology... Estimated frequency of gene 1:70 in non isolated population Incidence in isolated population 1:8000 ( Finnish) Exact incidence is unknown: 1.Published studies vary in the cohort of cases examined 2.Some severely affected babies die perinatally without definite diagnosis

5. Genetics: AR Mutation in PKHD1, chromosome 6P21 To date all kindereds with typical features of ARPKD have demonstrated linkage to this locus Over 350 mutations have been recognized ( 2009)

6. Genetics... Among the largest disease genes characterized to date in human genome (470 kb) Encodes for polyductin/fibrocystin protein This protein is localised in primary cilia mainly in the kidney To lesser extent in liver, pancrease and arterial wall.

8. Genetics... Genotype-phenotype correlation from type of mutation rather than the site of mutation Truncating mutation displays severe form Missense mutations are more frequent in less severe form

9. Clinical features: Flank masses HTN Urinary concentration defect Hyponatraemia Renal insufficiency Pulmonary hypoplasia HSM Oesophageal varices hypersplenism

10. Renal: Very rarely to be the cause of death in NN period Usually improving following recovery from respiratory problems Hyponatraemia is usually transient and related to the concentration defect Fluid restriction could sort low Na but?

11. Hypertension Unknown mechanism 80% of affected children ACE inhibitors,Ca channel blockers and beta blockers Normal renin and aldosterone peripheral activity May be related to local RAAS activation Needs more than one agent to be controlled

12. Case 1.... 35+3 premature Caucasian male NVD, breech Birth weight:2.3 kg Normal antenatal scan Both parents are under 30 No F/H of renal diseases

13. Case 1... Apgar of 1,9 @1 &5 minutes 48 hrs of IV Ab Needed initially CPAP, severe RD Ventilated with surfactant x 2 Right pneumothorax, needed chest drain

14. Case 1... Generalised oedema by D2 B/L large abdominal masses Oliguria,low Na, high urea and creatinine Urinalysis blood & protein +++ Abdominal US: B/L PKD, most likely ARPKD, coarse liver.

16. Case 1... Issues 1.Persistent HTN ( required 5 anti HTN& diuretics) 2.Poor weight gain 3.Renal failure 4.Family counselling

17. Case 2... 8 year old female Normal antenatal scan, no F/H of renal diseases 38/40, NVD RD, pneumothorax Discovered to have ARPKD at the age of 4 months Never needed dialysis

18. Case 2... Kept on conservative treatment Hypertension ( controlled by 2 anti HTN) No concern regarding liver Has LRD renal Tx from dad

19. Case 2... 3 months post renal Tx Frequent blood Tx Recurrent sepsis Poor graft function Massive spleenomegally

20. Case 2... Issues: 1.Graft nephrectomy 2.Haemodialysis 3.Combined liver-kidney Tx 4.Family disappointment

21. Diagnosis: Diagnostic criteria were proposed by Zerres etal: 1.US features typical of ARPKD( enlarged,ecchogenic kidneys with poor CMD and 2.One or more of the following: a) absence of renal cysts in both parents particularly if they are > 30 years old

22. Diagnosis... b) clinical, lab or radiological evidence of hepatic fibrosis c) hepatic pathology demonstrating ductal plate abnormality d) previous affected sibling e) parental consanguinity suggestive of AR inheritance

23. Diagnosis... Genetic testing is typically not required for patient with classic ARPKD Prenatal diagnosis in a family with at least one affected child via mutation analysis With identification and cloning of PKHD1, molecular analysis is now available

24. Neonatal large kidneys Differential diagnosis includes - ARPKD - ADPKD - Glomerulocystic disease - Diffuse cystic dysplasia Think about syndromes, e.g. Tuberous sclerosis, Zellweger syndrome Trisomy 13,etc…

25. Large NN kidneys Other causes - RVT - Congenital NS - Contrast nephropathy - Renal candidiasis - Glycogen storage disease - Leukaemia

26. Clinical features of cystic diseases presenting in the newborn period DiseaseInheritancUSSPathologyAssociatedanomalies ARPKDAR Large echogenic kidneys, microcysts, occasional macrocytes Fusiform dilatation CDs Hepatic fibrosis/ biliary dysgenesis ADPKDAD Large echogenic kidneys, occasional macrocysts (infants), multiple macrocysts (older) Cysts from any portion of nephron MV prolapse, cerebral aneurysm, AV malformation, hepatic cysts, pancreatic cysts GCKDAD/sporadic Large echogenic kidneys, occasional macrocysts Cystic dilatations of glomeruli May be syndromic Hepatic fibrosis 10% DiffusecysticdysplasiaSporadic Large echogenic kidneys, microcysts or macrocysts Immature nephron development, dysplastic features Usually syndromic

27. Clinical features suggesting ADPKD rather than ARPKD: Positive F/H Extrarenal cysts Cerebral aneurysm Asymptomatic presentation Unilateral presentation Haematuria UTIs

28. Renal Cysts Bilateral DiseaseUnilateral disease Large Kidney size Parenchyma small and echogenic Yes Simple cyst,ADPKD, GCKD MCKD Normal or small No IVP demonstrates Pyramidal Blush Medullary Cysts Cortical Cyst ADPKD or GCKD Parents has Cystic Kidney disease YesNo MCDNPH Medullary sponge Kidney Parents with ADPKD YesNo ADPKDLiver Disease YesNo ARPKD Consider ADPKD, NPH- type 2 and GCKD

29. Prognosis ARPKD Improved with NNIC - 30% severely affected † NN period - for those surviving 1 yr survival 75-90% 5 yr survival 70-88% Progression  ESRF - > 50% - time variable Common problems - feeding and growth failure - UTI - hepatic fibrosis - complications of RRT

30. Prognosis ARPKD... Portal HT not uncommon Significant risk for ascending bacterial cholangitis Hepatic complications are the main reason of death in a 14 year follow up study post renal Tx

31. Bergmann et al. (2005) Guay – Woodford and Desmond (2003) Capisonda et al. (2003) Roy et al. (1997) Zerres et al. (1996) Gagnadoux et al. (1989) Kaplan et al. (1989) Patients 18616631521153355 Age at diagnosis 23% prenatal 31% <1 mo 16% 1-12 mo 30% >1 yr 46% prenatal 27% <1 mo 11% 1-12mo 16% > 1yr 32% prenatal 23% < 1 mo 19% 1-2 mo 26% > 1 yr 85% < 1yr 15% >1yr 10% prenatal 41% <1mo 23% 1-12 mo 26% >1yr 33% <1 mo 55% 1-18 mo 12% 6-11yr 42% < 1 mo 42% 1-12 mo 16% <1yr Renal function variable Median age CRF 4.0 yr 29% ESRD ( by 10 yr) 13% ESRD51% GFR <80 16% ESRD 33% ESRD ( by 15yr) 10% ESRD42% GFR <80 ml/min/1.73m 2 21% ESRD 58% SC >100µmol/ml Hypertension (%on drug treatment ) 76% 53% during 1 st month 65%55%60% (by 15 yr ) 70%76%65% Evidence of Portal hypertension 44% 38% spleenomegaly 15% eosphageal varices 2% Ascites 15%37%23% (8/35)46%39%47% Survival rate 1 yr : 85% 5 yr : 84% 10 yr : 82 % 1 yr : 79% 5yr : 75% 1yr :87% 9 yr:80% NA1 yr:89% 3 yr : 88% 1yr :91 %1yr: 79% 10yr: 51 % 15 yr : 46% Death rate In the first year of life 15%8%13%26%9% 24%

32. To take home Significant phenotypic variability Neonatal period - respiratory - fluid balance and electrolytes - hypertension Prognosis improved with NNIC but progression to ESRF in >50%

33. To take home Portal HTN can develop with normal synthetic liver function Every patient with recurrent unexplained sepsis should be treated for cholangitis ( gram neg organisms) Dietetic input is crucial BP control could be a challenge