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

Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

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Page 1: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

Autosomal Recessive Polycystic Kidney Disease (ARPKD)

The disease with more than one face

Ihab Shaheen

Consultant Paediatric Nephrologist

RHSC- Glasgow

Page 2: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

Learning objectives:

• Epidemiology

• Genetics

• Clinical feature

• 2 Cases

• Differential diagnoses

• Prognosis

• Literature

• To take home

Page 3: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

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

Page 4: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

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

Page 5: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

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)

Page 6: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

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.

Page 7: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease
Page 8: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

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

Page 9: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

Clinical features:

• Flank masses

• HTN

• Urinary concentration defect

• Hyponatraemia

• Renal insufficiency

• Pulmonary hypoplasia

• HSM

• Oesophageal varices

• hypersplenism

Page 10: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

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?

Page 11: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

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

Page 12: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

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

Page 13: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

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

Page 14: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

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.

Page 15: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease
Page 16: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

Case 1...

• Issues

1. Persistent HTN ( required 5 anti HTN& diuretics)

2. Poor weight gain

3. Renal failure

4. Family counselling

Page 17: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

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

Page 18: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

Case 2 ...

• Kept on conservative treatment

• Hypertension ( controlled by 2 anti HTN)

• No concern regarding liver

• Has LRD renal Tx from dad

Page 19: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

Case 2 ...

3 months post renal Tx

• Frequent blood Tx

• Recurrent sepsis

• Poor graft function

• Massive spleenomegally

Page 20: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

Case 2 ...

Issues:

1. Graft nephrectomy

2. Haemodialysis

3. Combined liver-kidney Tx

4. Family disappointment

Page 21: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

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

Page 22: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

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

Page 23: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

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

Page 24: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

Neonatal large kidneys

• Differential diagnosis includes- ARPKD- ADPKD- Glomerulocystic disease- Diffuse cystic dysplasia

• Think about syndromes,e.g. Tuberous sclerosis , Zellweger syndromeTrisomy 13 ,etc…

Page 25: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

Large NN kidneys

• Other causes- RVT- Congenital NS- Contrast nephropathy- Renal candidiasis- Glycogen storage disease- Leukaemia

Page 26: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

Clinical features of cystic diseases presenting in the newborn period

Disease Inheritanc USS Pathology Associated

anomalies

ARPKD AR Large echogenic

kidneys, microcysts,

occasional macrocytes

Fusiform dilatation

CDs

Hepatic fibrosis/

biliary dysgenesis

ADPKD AD 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

GCKD AD/

sporadic

Large echogenic

kidneys, occasional

macrocysts

Cystic dilatations

of glomeruli

May be syndromic

Hepatic fibrosis

10%

Diffuse

cystic

dysplasia

Sporadic Large echogenic

kidneys, microcysts or

macrocysts

Immature nephron

development,

dysplastic features

Usually syndromic

Page 27: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

Clinical features suggesting ADPKD rather than ARPKD:

• Positive F/H

• Extrarenal cysts

• Cerebral aneurysm

• Asymptomatic presentation

• Unilateral presentation

• Haematuria

• UTIs

Page 28: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

Renal Cysts

Bilateral Disease Unilateral 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

Yes No

MCD NPH

Medullary sponge Kidney

Parents with ADPKD

Yes No

ADPKD Liver Disease

Yes No

ARPKD Consider ADPKD , NPH-type 2 and GCKD

Page 29: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

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

Page 30: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

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

Page 31: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

Bergmannet al. (2005)

Guay –Woodford and Desmond (2003)

Capisonda et al. (2003)

Roy et al. (1997)

Zerres et al. (1996)

Gagnadouxet al. (1989)

Kaplan et al. (1989)

Patients 186 166 31 52 115 33 55

Age at diagnosis 23% prenatal 31% <1 mo16% 1-12 mo30% >1 yr

46% prenatal 27% <1 mo11% 1-12mo16% > 1yr

32% prenatal 23% < 1 mo19% 1-2 mo26% > 1 yr

85% < 1yr15% >1yr

10% prenatal 41% <1mo23% 1-12 mo26% >1yr

33% <1 mo55% 1-18 mo12% 6-11yr

42% < 1 mo42% 1-12 mo16% <1yr

Renal function variable

Median age CRF 4.0 yr 29% ESRD ( by 10 yr)

13% ESRD 51% GFR <8016% ESRD

33% ESRD ( by 15yr)

10% ESRD 42% GFR <80 ml/min/1.73m221% ESRD

58% SC >100µmol/ml

Hypertension (%on drug treatment )

76%53% during 1st month

65% 55% 60% (by 15 yr )

70% 76% 65%

Evidence ofPortalhypertension

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%

NA 1 yr:89% 3 yr : 88%

1yr :91 % 1yr: 79% 10yr: 51 % 15 yr : 46%

Death rate In the first yearof life

15% 8% 13% 26% 9% 9% 24%

Page 32: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

To take home

• Significant phenotypic variability

• Neonatal period

- respiratory

- fluid balance and electrolytes

- hypertension

• Prognosis improved with NNIC but progression to ESRF in >50%

Page 33: Autosomal Recessive Polycystic Kidney Disease (ARPKD) The disease

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