Autosomal Recessive Polycystic Kidney
Disease (ARPKD)
The disease with more than one face
Ihab Shaheen
Consultant Paediatric Nephrologist
RHSC- Glasgow
Learning objectives:
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Epidemiology
Genetics
Clinical feature
2 Cases
Differential diagnoses
Prognosis
Literature
To take home
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
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
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)
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.
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
Clinical features:
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Flank masses
HTN
Urinary concentration defect
Hyponatraemia
Renal insufficiency
Pulmonary hypoplasia
HSM
Oesophageal varices
hypersplenism
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?
Hypertension
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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
Case 1....
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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
Case 1...
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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
Case 1...
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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.
Case 1...
• Issues
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Persistent HTN ( required 5 anti HTN& diuretics)
Poor weight gain
Renal failure
Family counselling
Case 2...
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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
Case 2 ...
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Kept on conservative treatment
Hypertension ( controlled by 2 anti HTN)
No concern regarding liver
Has LRD renal Tx from dad
Case 2 ...
3 months post renal Tx
• Frequent blood Tx
• Recurrent sepsis
• Poor graft function
• Massive spleenomegally
Case 2 ...
Issues:
1. Graft nephrectomy
2. Haemodialysis
3. Combined liver-kidney Tx
4. Family disappointment
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
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
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
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…
Large NN kidneys
• Other causes
- RVT
- Congenital NS
- Contrast nephropathy
- Renal candidiasis
- Glycogen storage disease
- Leukaemia
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
Clinical features suggesting ADPKD rather than ARPKD:
• Positive F/H
• Extrarenal cysts
• Cerebral aneurysm
• Asymptomatic presentation
• Unilateral presentation
• Haematuria
• UTIs
Renal Cysts
Bilateral Disease
Unilateral disease
Kidney size
Parenchyma small and
echogenic
Normal or
small
Large
Parents with
ADPKD
Yes
IVP demonstrates
Pyramidal Blush
Medullary
Cysts
Medullary sponge
Kidney
Parents has
Cystic
Kidney
disease
No
ADPKD
Liver Disease
Yes
Yes
ARPKD
Yes
MCKD
Cortical Cyst
ADPKD or
GCKD
No
No
Consider ADPKD , NPHtype 2 and GCKD
MCD
NPH
No
Simple cyst
,ADPKD,
GCKD
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
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
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
186
166
31
52
115
33
55
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% ESRD
51% GFR <80
16% ESRD
33% ESRD
( by 15yr)
10% ESRD
42% GFR <80
ml/min/1.73m
2
21% ESRD
58% SC
>100µmol/ml
Hypertension
(%on drug
treatment )
76%
53% during 1st 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%
NA
1 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%
9%
24%
To take home
• Significant phenotypic variability
• Neonatal period
- respiratory
- fluid balance and electrolytes
- hypertension
• Prognosis improved with NNIC but progression to
ESRF in >50%
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